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Carriers of NPC1L1 Inactivating Mutations Have Lower Coronary Heart Disease Risk, Researchers Say

NEW YORK (GenomeWeb) – Naturally occurring mutations that disrupt NPC1L1 protein function are associated with lower plasma low-density lipoprotein levels and a reduced risk of coronary heart disease, investigators from the Myocardial Infarction Genetics Consortium reported in the New England Journal of Medicine this week.

The team led by Massachusetts General Hospital's Sekar Kathiresan examined NPC1L1 gene exons in more than 7,000 coronary heart disease patients and nearly 15,000 controls to identify inactivating mutations that crop up in that gene naturally. They then genotyped the most common inactivating mutation they unearthed in a further 91,000 individuals. Mutation carriers, they reported, had lower LDL cholesterol levels than non-carriers and had a more than 50 percent decease in coronary heart disease risk.

"Protective mutations like the one we've just identified for heart disease are a treasure trove for understanding human biology," Kathiresan said in a statement. "They can teach us about the underlying causes of disease and point to important drug targets."

NPC1L1 is already a target of the lipid-lowering drug ezetimibe. But whether that drug also affects coronary heart disease risk is unknown.

For this study, Kathiresan and his colleagues extracted sequence data for the 20 protein-coding exons making up the NPC1L1 gene from samples from 22,092 participants in seven case-control studies and two prospective cohort studies who had undergone exome sequencing.

By aligning those reads to the human reference genome, the researchers identified 15 inactivating mutations such as nonsense, splice-site, and frameshift mutations. The researchers estimated that about one in 650 people is a carrier of an inactive allele. The most common inactivating mutation they identified was p.Arg406X, which had a minor allele frequency of 0.02 percent among participants of European ancestry.

They genotyped this variant in a further 22,590 people with coronary heart disease and 68,412 controls from nine independent sample sets to identify 48 additional heterozygous carriers.

By examining the cholesterol levels and other clinical factors measured by the various studies they drew upon, Kathiresan and his colleagues found that individuals who are carriers of NPC1L1 inactivating mutations had lower total cholesterol levels and LDL cholesterol in particular. Carriers of any inactivating mutation had a mean LDL cholesterol level 12 milligrams per deciliter lower than the levels of noncarriers — similar to what is achieved through ezetimibe treatment.

Carriers were also underrepresented among coronary heart disease patients. Only 11 of the nearly 30,000 heart disease patients had an inactivating mutation, while 71 of the 83,140 controls carried an inactivating mutation. Further, carriers of inactivating mutations have a 53 percent reduction in risk of coronary heart disease, as compared to non-carriers, the researchers reported.

This reduced risk, they added, was seen in both people of African and European descent, though the reduction was greater in Europeans, 57 percent versus 17 percent reduction in risk.

This, Kathiresan and his colleagues said, indicates that lifelong inactivation of NPC1L1 is protective against coronary heart disease.

They additionally argued that this increases the likelihood that pharmacological inhibition of NPC1L1 could reduce disease risk.

Still, they added that their finding that naturally occurring mutations disrupting NPC1L1 reduced disease risk doesn't necessarily mean that drugs like ezetimibe will, as people with the mutation have had it all their lives and drug treatment would likely start in adulthood.

"It's not possible to draw a direct conclusion about ezetimibe from this study," first author Nathan Stitziel said. "But we can say this genetic analysis gives us some confidence that targeting this gene should reduce the risk of heart attack. Whether ezetimibe specifically is the best way to target NPC1L1 remains an open question."

He adds that the ongoing Improved Reduction of Outcomes: Vytorin Efficacy International Trial, or IMPROVE­IT, is examining whether statins taken with ezetimibe is a more effective treatment strategy than statins alone at lowering coronary heart disease risk.

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