title: Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts.
abstract: OBJECTIVE
  To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.
  
  
  METHODS
  Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).
  
  
  METHODS
  Two large, prospective cohort studies in Denmark.
  
  
  METHODS
  We measured levels of uric acid and related covariables in 58,072 participants from the Copenhagen General Population Study and 10,602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.
  
  
  RESULTS
  Blood pressure and prospectively assessed ischaemic heart disease.
  
  
  RESULTS
  Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).
  
  
  CONCLUSIONS
  By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.
authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Warwick, UK.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Marianne
authors.initials: M
authors.lastname: Benn
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000235:genetics*; D015992:Body Mass Index; D003718:Denmark; D005260:Female; D006801:Humans; D033461:Hyperuricemia / Q000209:etiology / Q000235:genetics*; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood / Q000235:genetics*; D011446:Prospective Studies; D012044:Regression Analysis; D014527:Uric Acid / Q000097:blood*
chemical_list: D014527:Uric Acid