title: Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels.
abstract: OBJECTIVE
  To determine whether mutations in APOA1 affect levels of high-density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population.
  
  
  BACKGROUND
  Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A-I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death.
  
  
  METHODS
  We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case-control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA-I in human heterozygotes and functional effects of mutations in adenovirus-transfected mice.
  
  
  RESULTS
  We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 [95% confidence interval (CI): 1.6-6.5], 5.5 (95% CI: 2.6-11.7) and 2.5 (95% CI: 1.3-4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case-control study. Furthermore, the ratio of mutant S164 to WT A164 apoA-I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA-I, and this finding was confirmed in adenovirus-transfected mice.
  
  
  CONCLUSIONS
  A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.
authors: Department of Clinical Biochemistry, Rigshospitalet, Denmark.
authors: C L
authors: CL
authors: Haase
authors: R
authors: R
authors: Frikke-Schmidt
authors: B G
authors: BG
authors: Nordestgaard
authors: A K
authors: AK
authors: Kateifides
authors: D
authors: D
authors: Kardassis
authors: L B
authors: LB
authors: Nielsen
authors: C B
authors: CB
authors: Andersen
authors: L
authors: L
authors: Køber
authors: A H
authors: AH
authors: Johnsen
authors: P
authors: P
authors: Grande
authors: V I
authors: VI
authors: Zannis
authors: A
authors: A
authors: Tybjaerg-Hansen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics*; D016022:Case-Control Studies; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017202:Myocardial Ischemia / Q000097:blood* / Q000235:genetics* / Q000401:mortality; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL