title: Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.
abstract: OBJECTIVE
  Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI).
  
  
  RESULTS
  We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25-2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32-2.68) compared with a causal genetic odds ratio of 1.94 (1.40-1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38-2.02) observational and 2.23(1.48-3.35) causal (P for comparison = 0.21).
  
  
  CONCLUSIONS
  These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters.
authors.affiliation: Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Anders Berg
authors.initials: AB
authors.lastname: Jørgensen
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.forename: Anders Sode
authors.initials: AS
authors.lastname: West
authors.forename: Peer
authors.initials: P
authors.lastname: Grande
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; D000369:Aged, 80 and over; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A / Q000235:genetics*; D016022:Case-Control Studies; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
chemical_list: C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001054:Apolipoproteins A; D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol