Causal effects of body mass index on cardiometabolic traits and events : a Mendelian randomization analysis

Holmes, Michael V. and Lange, Leslie A. and Palmer, Tom and Lanktree, Matthew B. and North, Kari E. and Almoguera, Berta and Buxbaum, Sarah and Chandrupatla, Hareesh R. and Elbers, Clara C. and Guo, Yiran and Hoogeveen, Ron C. and Li, Jin and Li, Yun R. and Swerdlow, Daniel I. and Cushman, Mary and Price, Tom S. and Curtis, Sean P. and Fornage, Myriam and Hakonarson, Hakon and Patel, Sanjay R. and Redline, Susan and Siscovick, David S. and Tsai, Michael Y. and Wilson, James G. and van der Schouw, Yvonne T. and FitzGerald, Garret A. and Hingorani, Aroon D. and Casas, Juan P. and de Bakker, Paul I. W. and Rich, Stephen S. and Schadt, Eric E. and Asselbergs, Folkert W. and Reiner, Alex P. and Keating, Brendan J. (2014) Causal effects of body mass index on cardiometabolic traits and events : a Mendelian randomization analysis. American Journal of Human Genetics, 94 (2). pp. 198-208. ISSN 0002-9297

Abstract

Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.