title: LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals.
abstract: BACKGROUND
  Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear.
  
  
  METHODS
  We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis.
  
  
  RESULTS
  Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11-2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70-2.62) (P(comparison) = 0.03).
  
  
  CONCLUSIONS
  Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, The Copenhagen City Heart Study, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Christiane L
authors.initials: CL
authors.lastname: Haase
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
authors.forename: Abbas Ali
authors.initials: AA
authors.lastname: Qayyum
authors.forename: Jesper
authors.initials: J
authors.lastname: Schou
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology / Q000235:genetics; D008076:Cholesterol, HDL / Q000032:analysis / Q000097:blood* / Q000235:genetics; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003718:Denmark; D005260:Female; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012042:Registries; D055815:Young Adult
chemical_list: D008076:Cholesterol, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase