title: Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark.
authors.forename: Bo Kobberø
authors.initials: BK
authors.lastname: Lauridsen
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stender
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.affiliation: The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark anne.tybjaerg.hansen@regionh.dk.
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
mesh_terms: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000378:metabolism; D004359:Drug Therapy, Combination; D000069438:Ezetimibe / Q000627:therapeutic use; D005260:Female; D042882:Gallstones / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy; D007511:Ischemia / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D026901:Membrane Transport Proteins; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000235:genetics
chemical_list: C416946:ABCG8 protein, human; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D000069438:Ezetimibe
keywords: Cardiovascular diseases; Cholesterol; Genetics