• Am. J. Hum. Genet. · Feb 2014

    Observational Study

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

    • Michael V Holmes, Leslie A Lange, Tom Palmer, Matthew B Lanktree, Kari E North, Berta Almoguera, Sarah Buxbaum, Hareesh R Chandrupatla, Clara C Elbers, Yiran Guo, Ron C Hoogeveen, Jin Li, Yun R Li, Daniel I Swerdlow, Mary Cushman, Tom S Price, Sean P Curtis, Myriam Fornage, Hakon Hakonarson, Sanjay R Patel, Susan Redline, David S Siscovick, Michael Y Tsai, James G Wilson, Yvonne T van der Schouw, Garret A FitzGerald, Aroon D Hingorani, Juan P Casas, Paul I W de Bakker, Stephen S Rich, Eric E Schadt, Folkert W Asselbergs, Alex P Reiner, and Brendan J Keating.
    • Division of Transplantation, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA; Genetic Epidemiology Group, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK. Electronic address: michael.holmes@uphs.upenn.edu.
    • Am. J. Hum. Genet. 2014 Feb 6; 94 (2): 198-208.

    AbstractElevated 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.Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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