Abstract 17184: A Genetic Variant Mimicking the Effect of Ezetimibe Associates With Increased Risk of Gallstone Disease
Background: Nieman-Pick C1-Like Protein1 (NPC1L1) mediates cholesterol uptake from the intestine and bile into enterocytes and hepatocytes, respectively. A common variant in NPC1L1 (rs2072183), mimicking the effect of ezetimibe, an inhibitor of NPC1L1, has been associated with reduced plasma levels of low-density lipoprotein (LDL) cholesterol, and might therefore also associate with increased biliary cholesterol, a risk factor for gallstone disease. We tested the hypothesis that NPC1L1 (rs2072183) genotype was associated with low plasma LDL cholesterol levels, decreased risk of ischemic vascular disease, and a concomitant increased risk of symptomatic gallstone disease.
Methods: Using NPC1L1 (rs2072183) as a genetic proxy for treatment with ezetimibe, we studied 73,457 individuals from the Danish general population. Of these, 10,481 developed ischemic vascular disease and 3,874 developed symptomatic gallstone disease during up to 34 years of follow-up.
Results: NPC1L1 genotype was associated with stepwise reductions in plasma levels of LDL cholesterol of up to 1.6% (0.05 mmol/L) for CC versus GG-homozygotes (P-trend=3.5х10(-8)). Multifactorially adjusted hazard ratios (HRs) for ischemic vascular disease were 0.95(95% confidence interval, 0.87-1.03) for CG-heterozygotes and 0.93(0.86-1.01) for CC-homozygotes versus GG-homozygotes (P-trend=0.07). Corresponding HRs for symptomatic gallstone disease were 1.14(0.98-1.33) and 1.19(1.03-1.38) (P-trend=0.02).
Conclusion: A common genetic variant in NPC1L1, mimicking the effects of ezetimibe on LDL cholesterol levels, was associated with increased risk of symptomatic gallstone disease and with a trend towards reduced risk of ischemic vascular disease. These results raise the question whether long-term treatment with ezetimibe might increase the risk of symptomatic gallstone disease.
- © 2013 by American Heart Association, Inc.