Null alleles at NPC1L1, the therapeutic target for the LDL-lowering drug ezetimibe, and protection from coronary heart disease. N. Stitziel1, S. Kathiresan2, Myocardial Infarction Genetics Consortium 1) Division of Cardiology, Department of Medicine and Division of Statistical Genomics, Washington University School of Medicine, St. Louis MO; 2) Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.

   BACKGROUND: Ezetimibe lowers plasma low-density lipoprotein (LDL) cholesterol by inactivating the Niemann-Pick C1-Like 1 (NPC1L1) gene product. Though widely prescribed, it is unknown if ezetimibe therapy reduces risk for coronary heart disease; a phase III randomized controlled trial including >18,000 participants is ongoing to test this hypothesis. Human mutations that inactivate a gene encoding a drug target can mimic drug action and thus can be used to infer the potential efficacy of that drug. METHODS: We sequenced the exons of NPC1L1 in a total of 4,703 cases with early-onset coronary heart disease and 5,090 controls free of coronary heart disease, identified carriers of null alleles (nonsense, splice-site, or frameshift mutations), and tested the association of carrier status with early coronary heart disease. In replication analyses, we sequenced NPC1L1 in an additional 1,528 coronary heart disease cases and 3,820 controls and genotyped a specific null alleles - p.Arg406X - in 14,708 coronary heart disease cases and 24,628 controls. We also tested the association of carrier status with plasma lipids. RESULTS: In the discovery study, we identified four NPC1L1 null alleles carried by ten individuals. Carrier status was associated with an 89% reduced risk of early coronary heart disease (OR 0.11; 95% CI 0.01 to 0.88; P=0.01). The observation of reduced risk was replicated in independent samples (P=0.02). Combining discovery and replication, carriers had a 78% reduced risk for coronary heart disease (OR 0.22; 95% CI 0.08 to 0.63; P=9x10-4; 4 carriers among 20,939 cases and 36 carriers among 33,538 controls) as well as 15.5 mg/dl lower plasma LDL cholesterol (P=0.02). CONCLUSIONS: Naturally occurring mutations in humans that disrupt NPC1L1 function are associated with reduced risk for coronary heart disease and lower LDL cholesterol. .

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