Causal Associations of Adiposity and Body Fat Distribution with Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis

Caroline E. Dale, Ghazaleh Fatemifar, Tom M. Palmer, Jon White, David Prieto-Merino, Delilah Zabaneh, Jorgen E.L. Engmann, Tina Shah, Andrew Wong, Helen R. Warren, Stela McLachlan, Stella Trompet, Max Moldovan, Richard W. Morris, Reecha Sofat, Meena Kumari, Elina Hyppönen, Barbara J. Jefferis, Tom R. Gaunt, Yoav Ben-ShlomoAng Zhou, Aleksandra Gentry-Maharaj, Andy Ryan, Renée De Mutsert, Raymond Noordam, Mark J. Caulfield, J. Wouter Jukema, Bradford B. Worrall, Patricia B. Munroe, Usha Menon, Chris Power, Diana Kuh, Debbie A. Lawlor, Steve E. Humphries, Dennis O. Mook-Kanamori, Naveed Sattar, Mika Kivimaki, Jacqueline F. Price, George Davey Smith, Frank Dudbridge, Aroon D. Hingorani, Michael V. Holmes, Juan P. Casas

Research output: Contribution to journalArticlepeer-review

153 Citations (Scopus)

Abstract

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease. Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m2; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD). Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.

Original languageEnglish
Pages (from-to)2373-2388
Number of pages16
JournalCirculation
Volume135
Issue number24
DOIs
Publication statusPublished or Issued - 13 Jun 2017

Keywords

  • Mendelian randomization analysis
  • adiposity
  • body fat distribution
  • body mass index
  • coronary artery disease
  • stroke
  • waist-hip ratio

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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