TY - JOUR

T1 - Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease

AU - Lauridsen, Bo Kobberø

AU - Stender, Stefan

AU - Frikke-Schmidt, Ruth

AU - Nordestgaard, Børge G

AU - Tybjærg-Hansen, Anne

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - AIMS: Ezetimibe reduces plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1 (NPC1L1), the transporter responsible for cholesterol uptake from the intestine into enterocytes and from the bile into hepatocytes. We tested the hypothesis that genetic variation in NPC1L1, mimicking the effect of ezetimibe, was associated with reduced risk of ischaemic vascular disease (IVD) and with increased risk of symptomatic gallstone disease.METHODS AND RESULTS: We included 67 385 individuals from the general population. Of these, 5255 and 3886 individuals developed IVD or symptomatic gallstone disease, respectively, during follow-up from 1977 to 2013. We genotyped four common NPC1L1 variants, previously associated with reduced LDL cholesterol levels, thus mimicking the effect of ezetimibe, and calculated a weighted genotype score. With increasing genotype score, LDL cholesterol decreased stepwise up to 3.5% (0.12 mmol/L) and total cholesterol up to 1.9% (0.11 mmol/L) (P-trend: 2 × 10(-12) and 2 × 10(-9)). The cumulative incidence by age of IVD decreased, while that of symptomatic gallstone disease increased as a function of increasing genotype score (P-trend: 0.005 and 0.01). Hazard ratios for genotype scores ≥ 5.0 vs. <2.0 were 0.82 (95% confidence interval: 0.70-0.95) for IVD and 1.22 (0.99-1.49) for gallstone disease (P-trend across genotype scores: 0.004 and 0.01).CONCLUSION: Genetic variation in NPC1L1 is associated with a reduction in risk of IVD, with a corresponding reduction in LDL cholesterol, but with a concomitant increased risk of gallstone disease. These data support the hypothesis that treatment with ezetimibe protects against IVD but raise the question whether long-term treatment increases the risk of gallstone disease.

AB - AIMS: Ezetimibe reduces plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1 (NPC1L1), the transporter responsible for cholesterol uptake from the intestine into enterocytes and from the bile into hepatocytes. We tested the hypothesis that genetic variation in NPC1L1, mimicking the effect of ezetimibe, was associated with reduced risk of ischaemic vascular disease (IVD) and with increased risk of symptomatic gallstone disease.METHODS AND RESULTS: We included 67 385 individuals from the general population. Of these, 5255 and 3886 individuals developed IVD or symptomatic gallstone disease, respectively, during follow-up from 1977 to 2013. We genotyped four common NPC1L1 variants, previously associated with reduced LDL cholesterol levels, thus mimicking the effect of ezetimibe, and calculated a weighted genotype score. With increasing genotype score, LDL cholesterol decreased stepwise up to 3.5% (0.12 mmol/L) and total cholesterol up to 1.9% (0.11 mmol/L) (P-trend: 2 × 10(-12) and 2 × 10(-9)). The cumulative incidence by age of IVD decreased, while that of symptomatic gallstone disease increased as a function of increasing genotype score (P-trend: 0.005 and 0.01). Hazard ratios for genotype scores ≥ 5.0 vs. <2.0 were 0.82 (95% confidence interval: 0.70-0.95) for IVD and 1.22 (0.99-1.49) for gallstone disease (P-trend across genotype scores: 0.004 and 0.01).CONCLUSION: Genetic variation in NPC1L1 is associated with a reduction in risk of IVD, with a corresponding reduction in LDL cholesterol, but with a concomitant increased risk of gallstone disease. These data support the hypothesis that treatment with ezetimibe protects against IVD but raise the question whether long-term treatment increases the risk of gallstone disease.

KW - ATP-Binding Cassette Transporters

KW - Aged

KW - Anticholesteremic Agents

KW - Cholesterol, LDL

KW - Drug Therapy, Combination

KW - Ezetimibe

KW - Female

KW - Gallstones

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors

KW - Hypercholesterolemia

KW - Ischemia

KW - Lipid Metabolism

KW - Male

KW - Membrane Proteins

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Myocardial Infarction

KW - Risk Factors

KW - Stroke

U2 - 10.1093/eurheartj/ehv108

DO - 10.1093/eurheartj/ehv108

M3 - Journal article

C2 - 25841872

VL - 36

SP - 1601

EP - 1608

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 25

ER -