TY - JOUR
T1 - Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly
AU - Polisecki, Eliana
AU - Peter, Inga
AU - Simon, Jason S.
AU - Hegele, Robert A.
AU - Robertson, Michele
AU - Ford, Ian
AU - Shepherd, James
AU - Packard, Christopher
AU - Jukema, J. Wouter
AU - De Craen, Anton J.M.
AU - Westendorp, Rudi G.J.
AU - Buckley, Brendan M.
AU - Schaefer, Ernst J.
PY - 2010/5/1
Y1 - 2010/5/1
N2 - 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.
AB - 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.
KW - Cholesterol absorption
KW - Coronary heart disease
KW - Low density lipoprotein
KW - Single nucleotide polymorphism
KW - Statins
UR - http://www.scopus.com/inward/record.url?scp=77951069483&partnerID=8YFLogxK
U2 - 10.1194/jlr.P001172
DO - 10.1194/jlr.P001172
M3 - Article
C2 - 19752398
AN - SCOPUS:77951069483
SN - 0022-2275
VL - 51
SP - 1201
EP - 1207
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 5
ER -