CAMBRIDGE, Mass.—Loss-of-function mutations, in which a mutation causes a gene to have less-than-normal functioning levels or none at all, are a growing area of interest for investigators, as these naturally occurring mutations are both rare and generally convey helpful or protective effects. And a recent discovery has unveiled another such mutation and the effects it could have on cholesterol and heart disease. 
Researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital and other locations examined the DNA of more than 100,000 people, discovering a number of such mutations in their genes that lower LDL cholesterol levels. These mutations also serve to reduce an individual's risk of coronary heart disease by approximately 50 percent. The mutations disrupt a gene known as Niemann-Pick C1-Like 1 (NPC1L1), which coincidentally is the molecular target of ezetimibe, a drug approved by the U.S. Food and Drug Administration for the treatment of high LDL cholesterol.
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Read More“Protective mutations like the one we’ve just identified for heart disease are a treasure trove for understanding human biology,” said Sekar Kathiresan, Broad associate member, director of preventive cardiology at Massachusetts General Hospital and a senior author of the study. “They can teach us about the underlying causes of disease and point to important drug targets.”
NPC1L1 joins three other genes in which loss-of-function mutations that have protective effects against heart or metabolic disease: PCSK9 and AP0C3 have demonstrated protective effects against heart disease, while SLC30A8 has been found to offer protection against type 2 diabetes.
This work featured the expertise of the Broad Institute's Genomics Platform, which is led by co-author Stacey Gabriel, and significant support from the National Human Genome Research Institute. In sequencing the exomes of more than 20,000 people of European, African or South Asian descent, they discovered 15 distinct mutations in NPC1L1, all of which inactivate or dampen gene activity. Approximately one in 650 people carry one of these mutations. The mutations were then correlated with LDL levels.
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Read MoreUpon studying the genomes of another 91,000 people, the team found that those with inactivating mutations of NPC1L1 tend to have lower LDL levels than those without such mutations; they presented with reductions that averaged about 12 mg/dL, a 10-percent drop similar to what is seen in patients taking ezetimibe.
“When it comes to rare variant studies, there is simply no substitute for extremely large sample sizes,” said Gabriel. “This has become crystal clear through our work on NPC1L1 as well as several other similar projects here at the Broad. We now know the right path to get statistically robust results, and that’s the path we are on.”
While it is not yet confirmed if ezetimibe also lowers an individual's risk of heart disease, a randomized, controlled, multiyear trial has been underway to determine if such a correlation exists. Results from the IMPROVE IT trial are expected later this month.
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Read More“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.
The results of the team's work were published online Nov. 12 in an article in the New England Journal of Medicine titled “Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease.”
SOURCE: Broad Institute press release
