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

TY - JOUR

T1 - Obesity as a causal risk factor for deep venous thrombosis

T2 - a Mendelian randomization study

AU - Klovaite, Jolanta

AU - Benn, M

AU - Nordestgaard, B G

N1 - © 2014 The Association for the Publication of the Journal of Internal Medicine.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Objective: To test the hypothesis that obesity is causally associated with deep venous thrombosis (DVT). Design: A Mendelian randomization design. Setting: The Copenhagen General Population Study and the Copenhagen City Heart Study combined. Subjects: 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. Main outcome measure: First events of DVT with or without pulmonary embolism (PE). Analysis: 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. Conclusion: 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.

AB - Objective: To test the hypothesis that obesity is causally associated with deep venous thrombosis (DVT). Design: A Mendelian randomization design. Setting: The Copenhagen General Population Study and the Copenhagen City Heart Study combined. Subjects: 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. Main outcome measure: First events of DVT with or without pulmonary embolism (PE). Analysis: 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. Conclusion: 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Body Mass Index

KW - Denmark

KW - Female

KW - Genotype

KW - Humans

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Obesity

KW - Pulmonary Embolism

KW - Risk Factors

KW - Venous Thrombosis

KW - Young Adult

U2 - 10.1111/joim.12299

DO - 10.1111/joim.12299

M3 - Journal article

C2 - 25161014

SN - 0954-6820

VL - 277

SP - 573

EP - 584

JO - Journal of Internal Medicine

JF - Journal of Internal Medicine

IS - 5

ER -