title: Mutation in ABCA1 predicted risk of ischemic heart disease in the Copenhagen City Heart Study Population.
abstract: OBJECTIVE
  We tested whether heterozygosity for the K776N mutation (frequency: 0.4%) in ATP-binding cassette transporter A1 (ABCA1) predicted ischemic heart disease (IHD) in the Copenhagen City Heart Study population.
  
  
  BACKGROUND
  In a complex trait like IHD, genetic variation is considered to be conferred by common DNA polymorphisms, although rare mutations may have a larger impact. Tangier disease, a rare high-density lipoprotein cholesterol (HDL-C) deficiency syndrome with IHD, is caused by homozygous ABCA1 mutations.
  
  
  METHODS
  We analyzed blood samples from a large cohort study of 9,076 Danish individuals followed for 24 years (167,287 person-years), during which 1,033 incident IHD events occurred. The hypothesis was retested in an independent case-control study comparing 562 IHD patients with 3,103 controls.
  
  
  RESULTS
  The cumulative incidence of IHD as a function of age was increased in K776N heterozygotes compared with non-carriers (log-rank test: p = 0.005). At the age of 80 years, 48% of heterozygotes and 23% of non-carriers had IHD. Incidence rates in non-carriers and K776N heterozygotes were 61 and 157 per 10,000 person-years. The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5). Adjusting for HDL-C, or for smoking, diabetes, and hypertension did not change the result, suggesting that genotype predicted risk of IHD beyond that offered by HDL-C, and by other conventional risk factors. Similar trends were obtained in an independent case-control study.
  
  
  CONCLUSIONS
  Heterozygosity for an ABCA1 mutation (K776N) conferred two- to three-fold risk of IHD in 37 participants in the Copenhagen City Heart study.
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Peter
authors.initials: P
authors.lastname: Schnohr
authors.forename: Rolf
authors.initials: R
authors.lastname: Steffensen
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjaerg-Hansen
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D016022:Case-Control Studies; D003718:Denmark; D005260:Female; D005500:Follow-Up Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017202:Myocardial Ischemia / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters