title: Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.
abstract: BACKGROUND
  High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk of ischemic cardiovascular disease in the general population is unknown.
  
  
  METHODS
  Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7557 of these 10,797 participants.
  
  
  RESULTS
  Participants with nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol per liter (350 mg per deciliter) or more (hazard ratio for ischemic vascular disease, 0.43; 95% confidence interval [CI], 0.35 to 0.54; hazard ratio for ischemic heart disease, 0.40; 95% CI, 0.31 to 0.52). Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (P<0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations (P=0.009 and P=0.05, respectively), with corresponding risk reductions of 41% (hazard ratio, 0.59; 95% CI, 0.41 to 0.86; P=0.007) and 36% (hazard ratio, 0.64; 95% CI, 0.41 to 0.99; P=0.04).
  
  
  CONCLUSIONS
  Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. (Funded by the European Union and others.).
authors.affiliation: From Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen (A.B.J., R.F.-S., B.G.N., A.T.-H.), the Department of Clinical Biochemistry, Rigshospitalet (A.B.J., R.F.-S., A.T.-H.), the Department of Clinical Biochemistry (B.G.N.) and the Copenhagen General Population Study (R.F.-S., B.G.N., A.T.-H.), Herlev Hospital, and the Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.) - all in Copenhagen.
authors.forename: Anders Berg
authors.initials: AB
authors.lastname: Jørgensen
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
mesh_terms: D000328:Adult; D000368:Aged; D053305:Apolipoprotein C-III / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood; D059472:Exome; D005260:Female; D005838:Genotype; D006801:Humans; D015994:Incidence; D007511:Ischemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017202:Myocardial Ischemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood*
chemical_list: D053305:Apolipoprotein C-III; D008078:Cholesterol, LDL; D014280:Triglycerides