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ӳ����ý-led team reveals new genetic findings that link major pathway for triglyceride metabolism to risk of coronary artery disease

For decades, scientists have searched for the biological roots of coronary artery disease (CAD), the most common form of heart disease and the leading cause of death in the United States. LDL, a type of fat in the blood, emerged early on as a key player — high levels raise the risk of CAD and heart attack. Based on these insights, LDL-lowering drugs were first introduced in the late 1980’s and are now a staple of modern medicine.

The ӳ����ý of MIT and Harvard have expanded their collaboration with Bayer HealthCare to include cardiovascular genomics and drug discovery. The goal of this new part of the alliance is to leverage insights from human genetics to help create new cardiovascular therapies.

A team of investigators from the ӳ����ý, Massachusetts General Hospital and other leading biomedical research institutions has pinpointed rare mutations in a gene called APOA5 that increase a person’s risk of having a heart attack early in life. These mutations disable the APOA5 gene and also raise the levels in the blood of triglyceride-rich lipoproteins, a type of fat. The researchers’ findings, together with other recent genetic discoveries — specifically, the identification of protective mutations in the APOC3 gene that lower triglyceride levels and the risk of heart attack — refocus attention on abnormal triglyceride metabolism as an important risk factor for heart attack at any age. The work — the largest exome sequencing study yet published for any disease — appears this week in the journal Nature.

By combing through the DNA of more than 100,000 people, researchers at ӳ����ý, Massachusetts General Hospital, and elsewhere have identified rare, protective genetic mutations that lower the levels of LDL cholesterol — the so-called “bad” cholesterol — in the blood. The researchers’ findings, which appear online November 12 in the reveal that these naturally occurring mutations also reduce a person’s risk of coronary heart disease by about 50 percent. Remarkably, the mutations disrupt a gene called Niemann-Pick C1-Like 1 (NPC1L1) — the molecular target of the FDA-approved drug ezetimibe, often used as a treatment for high LDL.