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

Eliana Polisecki, Inga Peter, Jason S. Simon, Robert A. Hegele, Michele Robertson, Ian Ford, James Shepherd, Christopher Packard, J. Wouter Jukema, Anton J.M. De Craen, Rudi G.J. Westendorp, Brendan M. Buckley, Ernst J. Schaefer

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48 Scopus citations


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.

Original languageEnglish
Pages (from-to)1201-1207
Number of pages7
JournalJournal of Lipid Research
Issue number5
StatePublished - 1 May 2010
Externally publishedYes


  • Cholesterol absorption
  • Coronary heart disease
  • Low density lipoprotein
  • Single nucleotide polymorphism
  • Statins


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