Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A> G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart disease (CHD) and lipid-lowering response to pravastatin. We studied 5,804 elderly participants from the PROSPER study, who were randomized to pravastatin 40 mg/day or placebo and were followed on average for 3.2 years. In the adjusted gender-pooled analyses, homozygous carriers of the minor alleles at four NPC1L1 sites (-18A>C, L272L, V1296V, and U3_28650A> G, minor allele frequencies 0.15-0.33) had 2-8% higher LDL-cholesterol (LDL-C) levels at baseline than homozygous carriers of the common alleles (P < 0.05). Homozygotes for the rare alleles also had a significant increase in the risk of CHD events on trial ( range of hazard ratios 1.50-1.67; P < 0.02), regardless of the treatment regimen. The -133 A>G polymorphism and not other variants was associated with 6 month LDL-C lowering (P = 0.02). Our data indicate that variation in the NPC1L1 gene is associated with plasma total and LDL-C levels and CHD risk.-Polisecki, E., I. Peter, J. S. Simon, R. A. Hegele, M. Robertson, I. Ford, J. Shepherd, C. Packard, J. W. Jukema, A. J. M. DeCraen, R. G. J. Westendorp, B. M. Buckley, and E. J. Schaefer. Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly. J. Lipid Res. 2010. 51: 1201-1207.