• Yuan Lu, Kaveh Hajifathalian, Eric B Rimm, Majid Ezzati, and Goodarz Danaei.
• From the aDepartment of Global Health and Population, Harvard School of Public Health, Boston, MA; bChanning Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; cDepartment of Epidemiology, Harvard School of Public Health, Boston, MA; dDepartment of Nutrition, Harvard School of Public Health, Boston, MA; and eMRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
• Epidemiology. 2015 Mar 1; 26 (2): 153-62.

BackgroundThe prevalence of overweight and obesity is rising globally and together they constitute a major risk factor for coronary heart disease (CHD). Previous estimates of direct effects of high body mass index (BMI) on CHD did not consider an interaction between BMI and its mediators and did not include inflammatory biomarkers as potential mediators.MethodsWe analyzed data from 9 prospective cohort studies with 58,322 participants and 9,459 CHD events and decomposed the total effects into natural direct and indirect effects using a 2-stage regression model. We examined overweight (BMI = 25 to <30 kg/m) separately. We pooled hazard ratios using random-effects models and calculated the percentages of excess relative risk mediated by blood pressure, cholesterol, glucose, fibrinogen and high-sensitive C-reactive protein.ResultsThere was no interaction between BMI and its mediators in the multiplicative scale (P < 0.05 for all). Blood pressure was the most important mediator. The percentage of excess relative risk of overweight (versus normal BMI, 20 to <25 kg/m) mediated was 28% for blood pressure, 10% for blood glucose, and 14% for cholesterol. The same percentages for obesity were 37% for blood pressure, 17% for blood glucose, and 6% for cholesterol. The percentage mediated through all three metabolic risk factors together was 47% (95% confidence interval = 33%-63%) for overweight and 52% (38%-68%) for obesity. Fibrinogen mediated 6% to 9% and high-sensitive C-reactive protein mediated 6% to 8% of the excess relative risk for overweight and obese participants.ConclusionsMetabolic mediators explain about half of the adverse effects of high BMI on CHD. The role of inflammatory and prothrombotic biomarkers is much smaller than that of metabolic factors.

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