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 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.
Polisecki
Eliana
E
Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. eliana.polisecki@tufts.edu
Peter
Inga
I
Simon
Jason S
JS
Hegele
Robert A
RA
Robertson
Michele
M
Ford
Ian
I
Shepherd
James
J
Packard
Christopher
C
Jukema
J Wouter
JW
de Craen
Anton J M
AJ
Westendorp
Rudi G J
RG
Buckley
Brendan M
BM
Schaefer
Ernst J
EJ
D000368:Aged; D000369:Aged, 80 and over; D003327:Coronary Disease / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000627:therapeutic use; D012306:Risk; D016896:Treatment Outcome
D008074:Lipoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D017035:Pravastatin