/ en /news/study-reveals-links-between-blood-vessel-biology-and-heart-disease-risk <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source 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class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Wed, 07 Feb 2024 16:50:22 +0000 tulrich@broadinstitute.org 5556406 at /news/more-diverse-datasets-lead-better-genetic-risk-prediction-heart-disease <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=wRDlSPXz 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Thu, 06 Jul 2023 15:00:00 +0000 leah@broadinstitute.org 1282446 at /news/lipocyte-profiler-metabolic-biology-tool <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Fri, 30 Jun 2023 14:30:09 +0000 makenziekohler 1282386 at /news/broad-discovery-center-cambridge-opens-public-october <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=wRDlSPXz 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Mon, 19 Sep 2022 14:53:09 +0000 kzusi@broadinstitute.org 1195701 at /news/single-cell-map-heart-failure-suggests-possible-therapeutic-targets <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Wed, 22 Jun 2022 18:03:24 +0000 adicorat 1136501 at /news/single-cell-map-heart-reveals-wide-cellular-diversity <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=wRDlSPXz 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Thu, 04 Jun 2020 15:04:05 +0000 Corie Lok 630396 at /news/curbing-inflammation-could-reduce-heart-disease-risk-linked-blood-disorder <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=wRDlSPXz 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Wed, 13 Nov 2019 03:23:42 +0000 leah@broadinstitute.org 625076 at /news/calculating-genetic-risk-obesity <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Thu, 18 Apr 2019 14:48:11 +0000 kzusi@broadinstitute.org 504271 at /news/depth-polygenic-risk-scoring <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Mon, 27 Aug 2018 14:44:58 +0000 leah@broadinstitute.org 340086 at /news/predicting-risk-common-deadly-diseases-millions-genetic-variants <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" class="datetime">February 7, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Study reveals links between blood vessel biology and heart disease risk</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>Genetic alterations in cells lining blood vessels contribute to coronary artery disease, with implications for diagnostic and treatment strategies</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Brigham and Women's Hospital Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-02-07T11:50:22-05:00" title="Wednesday, February 7, 2024 - 11:50" class="datetime">February 7, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=ZLVFlUHz 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=qpy_aeZ5 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=Tu2SOWKY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=pmycP9ra 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/blood_vessel_endothelial_cells_NIHImageGallery_Flickr_26172287304_2bf86e6160_k.jpg?itok=d_8Zf7Ro" alt="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." title="Endothelial cells from blood vessels, stained red and blue in a flourescent microscope image." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Christopher V. Carman and Roberta Martinelli, Harvard Medical School </div> <div class="media-caption__description"> Microscopy image of cells lining blood vessel walls (red and blue) </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/614/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/rajat-gupta">Rajat Gupta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/cardiovascular-disease">Cardiovascular Disease Initiative</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=0yTVJ7o7 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=fWcYX4uO 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=wRDlSPXz 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/HeartDiseaseGeneticsStudy_Graphic_Story_Final.png?h=9423a5c0&amp;itok=CK8PdgHJ" alt="Zayna Sheikh" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/massive-international-study-uncovers-genes-involved-heart-disease" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Massive international study uncovers genes involved in heart disease</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=n-9-Ydhk 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=iqMiz6Eg 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=PW6QGmvh 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2016/PerturbSeq_MainImage-v3.png?itok=WwROMUny" alt typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/crispr-based-single-cell-genetics-platform-developed-broad-institute-and-ucsf-scientists" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">CRISPR-based single-cell genetics platform developed by ӳ����ý and UCSF scientists enables rapid analysis of critical gene networks </span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Over the past 15 years, researchers have identified hundreds of regions in the human genome associated with heart attack risk. However, researchers lack efficient ways to explore how these genetic variants are molecularly connected to cardiovascular disease, limiting efforts to develop therapeutics. To streamline analysis of hundreds of genetic variants associated with coronary artery disease (CAD), a team of researchers led by investigators from Brigham and Women’s Hospital (BWH), in collaboration with the ӳ����ý of MIT and Harvard and Stanford Medicine, combined multiple sequencing and experimental techniques to map the relationship between known CAD variants and the biological pathways they impact. In a study published in <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>, the researchers applied this technique to endothelial cells, which line blood vessels. The team found that a key biological mechanism involved in a rare vascular disease may influence CAD risk.</p> <p>“Studying how hundreds of regions of the genome, individually or in groups, influence risk of heart attack can be a painstaking process,” said corresponding author <a href="/node/516151">Rajat Gupta</a> of the Divisions of Genetics and Cardiovascular Medicine at BWH&nbsp;and the <a href="/node/8510">Cardiovascular Disease Initiative</a> at ӳ����ý. “We decided we needed to have better maps showing how genetic variants affect gene expression and how genes affect biological function. If we could combine those two kinds of maps, we could make the bigger connection from variant to biological function.”</p> <p>The mapping technique developed by the researchers is called the Variant-to-Gene-to-Program (V2G2P) approach. First, in collaboration with researchers at Stanford Medicine, the researchers&nbsp;–&nbsp;including co-first authors&nbsp;Gavin Schnitzler of BWH and ӳ����ý and&nbsp;Helen Kang of Stanford Medicine –&nbsp;matched CAD loci previously identified through genome-wide association studies to genes impacted by these genetic variants. Then, they used CRISPRi-Perturb-seq, a technology developed at ӳ����ý, to “delete” thousands of CAD-associated genes, one at a time, and to examine how each deletion impacted the expression of all the other genes in that cell. In total, the researchers sequenced 215,000 endothelial cells to determine how 2,300 “deletions” influenced expression of 20,000 other genes in each cell. With applied machine learning algorithms, they were able to identify the biological mechanisms that consistently appeared to be related to CAD-associated variants.</p> <p>In particular, the researchers found that 43 of 306 of the CAD-associated variants in endothelial cells were linked to genes in the cerebral cavernous malformations (CCM) signaling pathway. CCM is a rare, devastating vascular disease that impacts the brain, but the researchers hypothesized that smaller, subtler mutations in the genes involved in CCM may contribute to CAD risk by affecting vascular inflammation, thrombosis, and the structural integrity of the endothelium. Moreover, the researchers highlighted a previously unrecognized role for the <em>TLNRD1</em> gene in regulating the CCM pathway alongside other known CCM regulators and hypothesized that <em>TLNRD1</em> may be involved in both CAD, a common disease, and CCM, a rare one. &nbsp;</p> <p>Going forward, the researchers hope to study patients with endothelial CAD-associated variants as well as CCM patients to determine whether there are distinct opportunities for treating these populations. For the latter, the researchers are interested in determining whether further investigation into <em>TLNRD1</em> can lead to better forms of genetic testing and risk stratification.&nbsp;</p> <p>This study focused on endothelial cells, which line blood vessels and are increasingly understood to influence CAD risk. It examined endothelial mechanisms unrelated to lipid metabolism (a known driver of CAD risk with effective therapies, like statins) in hopes of uncovering other mechanisms driving CAD risk for which therapies may yet be developed.&nbsp;</p> <p>“Now that we know more about this collection of endothelial cell variants, we can return to patients who have them to see if they have different clinical features or respond differently to the therapies we are already using,” Gupta said. “We are also focused on this study’s implications for CCM patients. It was a coincidence that from this genetic screen designed to look at coronary disease, we implicated new genes for a rare vascular disease, CCM. Perhaps now we can better describe the risk factors and pathways that drive it.”</p> <p>Beyond CAD and CCM, the researchers emphasize that the V2G2P approach can be used to explore the biological mechanisms driving any disease for which a cell-type relevant to that disease can be genetically modified in the lab.</p> <p>“It was remarkable that this unbiased, systematic approach — in which we deleted all candidate CAD genes in a single experiment — pointed us straight to new genes and pathways that had escaped notice. This approach will be a powerful strategy for studying many other diseases where genetic risk factors remain to be discovered,” said co-corresponding author Jesse Engreitz,assistant professor of genetics at Stanford Medicine.</p> <p><em>Adapted from <a href="https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=4646" target="_blank">a press release issued by Brigham and Women's Hospital</a>, a founding member of the Mass General Brigham healthcare system.</em></p> <p><iframe allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen frameborder="0" height="315" src="https://www.youtube.com/embed/qzV-FJyHn_0?si=_64nZRq6c1yI4mjk&amp;start=1528" title="YouTube video player" width="560"></iframe></p> <p><em>Rajat Gupta talks about his work studying the biology of coronary artery disease during <a href="https://youtu.be/qzV-FJyHn_0?si=HuaGIwCB4WUET6FP" target="_blank">a 2023 ӳ����ý Discovery Series event</a>.</em></p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the Variant-to-Function Initiative at ӳ����ý; the&nbsp;National Heart, Lung, and Blood Institute; the National Human Genome Research Institute, ӳ����ýIgnite, and other sources.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Schnitzler GK, Kang H,&nbsp;et al. “Mapping the convergence of genes for coronary artery disease onto endothelial cell programs.” <a href="https://www.nature.com/articles/s41586-024-07022-x" target="_blank"><em>Nature</em></a>. DOI: 10.1038/s41586-024-07022-x.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/cardiovascular-disease" hreflang="en">Cardiovascular disease</a></div> <div class="field__item"><a href="/broad-tags/heart-disease" hreflang="en">Heart Disease</a></div> <div class="field__item"><a href="/broad-tags/machine-learning-0" hreflang="en">Machine Learning</a></div> <div class="field__item"><a href="/broad-tags/crispr" hreflang="en">CRISPR</a></div> </div> </div> </div> </div> </div> Mon, 13 Aug 2018 15:00:51 +0000 kzusi@broadinstitute.org 329356 at