Obesity as a causal risk factor for deep venous thrombosis: a Mendelian randomization study

ObjectiveTo test the hypothesis that obesity is causally associated with deep venous thrombosis (DVT). DesignA Mendelian randomization design. SettingThe Copenhagen General Population Study and the Copenhagen City Heart Study combined. SubjectsBody mass index (BMI) measurements were available for 87574 individuals of Danish descent from the adult general population. All subjects completed questionnaires and were genotyped for the FTO rs9939609 variant. Main outcome measureFirst events of DVT with or without pulmonary embolism (PE). AnalysisThe results were assessed using Cox regression, instrumental variable analysis and Poisson regression. ResultsObservationally, 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). FTOAA 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 1kgm(-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 >60years and homozygous for Factor V Leiden) was 35% in obese individuals and 18% in normal-weight individuals. ConclusionA 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.