Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease

Abstract

Background Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann–Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. Methods We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. Results With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). Conclusions Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.)

Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

“…However, we validated these genetic variants as being strongly associated with “gold-standard” measures of insulin sensitivity, with multiple insulin-resistance related diseases, including a severe form of insulin-resistant partial lipodystrophy, and showed overlap with monogenic insulin resistance genes. Thus, approaches to leverage additional sources of evidence to prioritise genomic variation (such as multiple phenotypes or putative functional class76) represent a powerful use of extant genetic association results to advance understanding of biology previously intractable to conventional strategies.…”

Genetics of coronary artery disease: discovery, biology and clinical translation

“…For example, inactivating mutations in the NPC1L1 gene were associated with decreased LDL cholesterol and risk of CAD. 72 A subsequent report from a randomized controlled trial of the drug ezetemibe, which inhibits the protein product of NPC1L1 to decrease cholesterol absorption, confirmed efficacy in cardiovascular event reduction. 73 By contrast, despite promising observational epidemiology and animal model evidence, 74,75 lipoprotein-associated phospholipase A 2 (Lp-PLA2) inhibitors proved ineffective in multiple trials involving over 28,000 patients.…”

Genetics of Coronary Artery Disease

“…One of these, p.Arg406X, in a much larger replication study was found to be associated with a 10% lower LDL-C and a 50% decrease in CAD risk. 50 Similarly, Lauridsen et al 51 , in a single-center study of the general population, included 67 385 individuals; of them, 5255 and 3886 developed incident ischemic vascular disease and symptomatic gallstone disease, respectively. Using a genetic score of common variants in NPC1L1, mimicking the effect of ezetimibe, they showed that these variants were associated with lifelong, stepwise reductions in LDL-C levels of ≤3.5%, with a corresponding 18% reduction in risk of CVD and a 22% increase in risk of symptomatic gallstone disease.…”