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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.

“Protective mutations like the one we’ve just identified for heart disease are a treasure trove for understanding human biology,” said Sekar Kathiresan, a senior author of the study, ӳ����ý associate member, and director of preventive cardiology at Massachusetts General Hospital. “They can teach us about the underlying causes of disease and point to important drug targets.”

Over the past several years, evidence has been mounting that certain loss-of-function mutations — mutations that reduce or completely eliminate a gene’s ability to work — can, at the same time, protect against disease. With this latest discovery, the list now stands at four genes that have been found to offer protective effects against either heart or metabolic disease. (The genes PCSK9, AP0C3, and now NPC1L1 have been found to protect against heart disease, and SLC30A8 has been shown to protect against type 2 diabetes.)

The scientific community is interested in these protective mutations not only because of what they can reveal about the biological basis of disease, but also for their ability to suggest potential paths toward new therapeutics. From a pharmaceutical perspective, it is much more feasible to develop a drug that disables, rather than activates, a gene.

Kathiresan’s long-standing interest in the genetics of blood cholesterol and heart disease first led him to uncover rare mutations in the NPC1L1 gene in just a handful of patients. He wondered if other patients carried similar mutations, so he set off on a massive hunt.

With the combined expertise of ӳ����ý’s Genomics Platform, led by Stacey Gabriel, and major support from the National Human Genome Research Institute, Kathiresan and his colleagues sequenced the exomes (the protein-coding portions of the genome) of over 20,000 people of European, African, or South Asian ancestry. They discovered 15 distinct mutations in NPC1L1, all of which serve to inactivate or dampen gene activity. Roughly 1 in 650 people carries one of these inactivating NPC1L1 mutations.

“When it comes to rare variant studies, there is simply no substitute for extremely large sample sizes,” said co-author Gabriel, director of ӳ����ý’s Genomics Platform. “This has become crystal clear through our work on NPC1L1 as well as several other similar projects here at the ӳ����ý. We now know the right path to get statistically robust results, and that’s the path we are on.”

After defining the mutational landscape of NPC1L1 in the initial study group of 20,000 people, Kathiresan and his colleagues correlated those mutations with LDL levels. The researchers examined the genomes of another 91,000 people and found that those with inactivating mutations in NPC1L1 tended to have lower LDL levels than those without such mutations. The reductions averaged about 12mg/dL, a 10 percent drop that is similar to what is seen in patients receiving ezetimibe therapy.

Individuals who carry inactivating NPC1L1 mutations also have a lower risk of coronary heart disease — roughly half the risk compared to those individuals without those mutations.

It is not yet definitively known if ezetimibe, which lowers LDL, also lowers the risk of heart disease. A large randomized, controlled clinical trial called IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT; ClinicalTrials.gov Identifier NCT00202878) has been underway for the last several years to explore this very question. Results from that trial are scheduled to be released later this month.

“Our genetic data are quite compelling, and lend strength to the idea that — based on what we know about the biology — ezetimibe should work to lower heart disease risk,” said Kathiresan.

But Kathiresan points out one important caveat: Naturally occurring mutations work over the course of a person’s lifetime, whereas a drug such as ezetimibe is usually given late in life. This relatively short time frame may not be long enough for the drug to impact disease risk.

While a genetic study like this one cannot directly address the safety and efficacy of a drug — only randomized, controlled clinical trials can do that — the current work lends further support to the decades-old notion that lowering LDL levels, which are often used as a marker for future disease risk, can also reduce a person’s chances of developing coronary heart disease.

“We know that LDL is one of the key drivers for coronary heart disease, and our NPC1L1 results give even more credence to that idea,” said Kathiresan.

About the ӳ����ý of Harvard and MIT

The Eli and Edythe L. ӳ����ý of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The ӳ����ý seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. ӳ����ý, the ӳ����ý includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the ӳ����ý, go to .