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Publication . Article . 2021

Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis.

Dipender Gill; Verena Zuber; Jesse Dawson; Jonathan Pearson-Stuttard; Alice R Carter; Eleanor Sanderson; Ville Karhunen; +8 Authors
Open Access   English  
Abstract Background Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood. Methods Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke. Results The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% −23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI −20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome. Conclusions Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.
Subjects by Vocabulary

Microsoft Academic Graph classification: Waist–hip ratio Internal medicine medicine.medical_specialty medicine business.industry business Diabetes mellitus medicine.disease Blood pressure Mendelian randomization Odds ratio Coronary artery disease Obesity Body mass index


Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, Nutrition & Dietetics, CORONARY-HEART-DISEASE, PLEIOTROPIC GENETIC-VARIANTS, OBESITY, ASSOCIATION, OVERWEIGHT, PREVENTION, PATHWAYS, 2-STEP, LEVEL, 11 Medical and Health Sciences, 13 Education, Article, /692/499, /692/699/75, /45/43, Article, /692/499, /692/699/75, /45/43, Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Risk factors, Cardiovascular diseases