Mediators of the Effect of Body Mass Index on Coronary Heart Disease Decomposing Direct and Indirect Effects

Background: The 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. Methods: We 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(2)) 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. Results: There 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(2)) 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. Conclusions: Metabolic 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.