title: Obesity as a causal risk factor for deep venous thrombosis: a Mendelian randomization study.
abstract: OBJECTIVE
  To test the hypothesis that obesity is causally associated with deep venous thrombosis (DVT).
  
  
  METHODS
  A Mendelian randomization design.
  
  
  METHODS
  The Copenhagen General Population Study and the Copenhagen City Heart Study combined.
  
  
  METHODS
  Body mass index (BMI) measurements were available for 87, 574 individuals of Danish descent from the adult general population. All subjects completed questionnaires and were genotyped for the FTO rs9939609 variant.
  
  
  METHODS
  First events of DVT with or without pulmonary embolism (PE).
  
  
  METHODS
  The results were assessed using Cox regression, instrumental variable analysis and Poisson regression.
  
  
  RESULTS
  Observationally, the risk of DVT increased with increasing BMI (P-trend < 0.0001). The multivariable-adjusted hazard ratio [95% confidence interval (CI)] for DVT was 1.3 (1.1-1.6) in overweight, 1.8 (1.4-2.2) in moderately obese and 3.4 (2.6-4.6) in severely obese compared with normal-weight individuals. For DVT complicated by PE, corresponding hazard ratios (95% CI) were 1.2 (0.8-1.8), 2.1 (1.3-3.5) and 5.1 (2.8-9.2). FTO AA versus TT genotype was associated with a 2.4% increase in BMI with hazard ratios (95% CI) of 1.09 (0.95-1.25) for DVT and 1.54 (1.12-2.10) for DVT complicated by PE. In instrumental variable analysis, the causal odds ratio (95% CI) for an increase in BMI of 1 kg m(-2) was 1.13 (0.92-1.39) for DVT alone and 1.86 (1.14-3.02) for DVT complicated by PE. The absolute 10-year risk of DVT in a high-risk group (i.e. those aged >60 years and homozygous for Factor V Leiden) was 35% in obese individuals and 18% in normal-weight individuals.
  
  
  CONCLUSIONS
  A strong observational association between obesity and DVT with or without PE, supported by a direct genetic association between the obesity-specific locus FTO and DVT with PE, implies that obesity is likely to be causally associated with DVT.
authors.affiliation: Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Klovaite
authors.forename: M
authors.initials: M
authors.lastname: Benn
authors.forename: B G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009765:Obesity / Q000150:complications* / Q000453:epidemiology; D011655:Pulmonary Embolism / Q000453:epidemiology; D012307:Risk Factors; D020246:Venous Thrombosis / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D055815:Young Adult
keywords: Mendelian randomization analysis; body mass index; deep venous thrombosis; general population