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

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  • Michael V. Holmes
  • Leslie A. Lange
  • 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
  • Brendan J. Keating
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<mark>Journal publication date</mark>6/02/2014
<mark>Journal</mark>American Journal of Human Genetics
Issue number2
Volume94
Number of pages11
Pages (from-to)198-208
Publication StatusPublished
<mark>Original language</mark>English

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.

Bibliographic note

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