title: The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease.
abstract: OBJECTIVE
  The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions.
  
  
  BACKGROUND
  High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation.
  
  
  METHODS
  A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated.
  
  
  RESULTS
  Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score ≥8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score ≥8.0 versus <2.0.
  
  
  CONCLUSIONS
  Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter.
authors.affiliation: Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stender
authors.affiliation: Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark.
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.affiliation: Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark. Electronic address: anne.tybjaerg.hansen@regionh.dk.
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000097:blood / Q000235:genetics*; D000368:Aged; D003718:Denmark / Q000453:epidemiology; D005260:Female; D042882:Gallstones / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D015995:Prevalence
chemical_list: C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins
keywords: ABCG5; ABCG8; cholesterol; gallstones; myocardial infarction