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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #256117
Title: Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly

Author
item POLISECKI, ELIANA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item PETER, INGA - Mount Sinai School Of Medicine
item HEGELE, ROBERT - Robarts Research Institute
item ROBERTSON, MICHELE - University Of Glasgow
item FORD, IAN - University Of Glasgow
item SHEPARD, JAMES - Schering-Plough Research
item PACKARD, CHRISTOPHER - Schering-Plough Research
item JUKEMA, WOUTER - Leiden University Medical Center
item DE CRAEN, ANTON - Leiden University Medical Center
item WESTENDORPH, RUDI - Leiden University Medical Center
item BUCKLEY, BRENDAN - Cork Institute Of Technology
item SCHAEFER, ERNST - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/10/2010
Publication Date: 5/20/2010
Citation: Polisecki, E., Peter, I., Hegele, R., Robertson, M., Ford, I., Shepard, J., Packard, C., Jukema, W.J., De Craen, A., Westendorph, R.G., Buckley, B.M., Schaefer, E.J. 2010. Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly. Journal of Lipid Research. 51:1201-1207.

Interpretive Summary: Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. We tested whether five genetic variants of this protein (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) had effects on plasma cholesterol and triglyceride levels, and heart disease in 5,804 elderly subjects half of whom received pravastatin 40 mg/day. In this analysis those individuals with the four NPC1L1 variants (-18A>C, L272L, V1296V, and U3_28650A>G) had about 5% higher levels of low density lipoprotein or LDL cholesterol (LDL-C) levels at baseline than those without these variants (P < 0.05). These subjects also had a significant increase of about 50% in heart disease risk during the trial, regardless of whether they received statin or not. Moreover those with the -133 A>G variant was associated with greater LDL cholesterol lowering than those who did not have this variant. Our data indicate that variation in the NPC1L1 gene is associated with plasma total and LDL cholesterol levels and heart disease risk.

Technical Abstract: 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 prava¬statin 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.