Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis - PubMed (original) (raw)

Observational Study

. 2014 Feb 6;94(2):198-208.

doi: 10.1016/j.ajhg.2013.12.014. Epub 2014 Jan 23.

Leslie A Lange 2, Tom Palmer 3, Matthew B Lanktree 4, Kari E North 5, Berta Almoguera 6, Sarah Buxbaum 7, Hareesh R Chandrupatla 6, Clara C Elbers 8, Yiran Guo 6, Ron C Hoogeveen 9, Jin Li 6, Yun R Li 6, Daniel I Swerdlow 10, Mary Cushman 11, Tom S Price 12, Sean P Curtis 13, Myriam Fornage 14, Hakon Hakonarson 6, Sanjay R Patel 15, Susan Redline 15, David S Siscovick 16, Michael Y Tsai 17, James G Wilson 18, Yvonne T van der Schouw 19, Garret A FitzGerald 12, Aroon D Hingorani 10, Juan P Casas 20, Paul I W de Bakker 21, Stephen S Rich 22, Eric E Schadt 23, Folkert W Asselbergs 24, Alex P Reiner 25, Brendan J Keating 26

Affiliations

Observational Study

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

Michael V Holmes et al. Am J Hum Genet. 2014.

Erratum in

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.

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

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Figures

Figure 1

Figure 1

Association between the BMI GS and Cardiometabolic Traits Effect estimates represent the beta (plotted) or regression (tabulated) coefficients (±95% CI) per 1-unit increase in weighted GS. The GS consisted of 14 SNPs taken from Guo et al. For log-transformed variables (marked by an asterisk), the regression coefficients are presented as a percent difference in the geometric mean.

Figure 2

Figure 2

Association between the BMI GS and Cardiometabolic Events Effect estimates represent the OR (±95% CI) for each outcome per 1-unit increase in weighted GS. The GS consisted of 14 SNPs (taken from Guo et al.23) that associated with a 1.08 kg/m2 increase in BMI (Figure 1).

Figure 3

Figure 3

Observational and Instrumental Variable Estimates of the Effect of BMI on Cardiometabolic Traits Effect estimates represent the beta (plotted) or regression (tabulated) coefficients (±95% CI) per 1 kg/m2 increase in BMI. Observational estimates were adjusted for age, sex, and study. For log-transformed variables (marked by an asterisk), the summary estimates are presented as a percent difference in the geometric mean. Causal estimates were derived from instrumental variable (IV) analysis.

Figure 4

Figure 4

Observational and Instrumental Variable Estimates of the Effect of BMI on Cardiometabolic Events Effect estimates represent the OR (±95% CI) per 1 kg/m2 increase in BMI. Observational estimates were adjusted for age, sex, and study. Causal estimates were derived from instrumental variable (IV) analysis.

Figure 5

Figure 5

Meta-analysis of Studies Investigating the Effect of BMI on CHD through Mendelian Randomization Analysis Effect estimates represent the OR (±95% CI) per 1 kg/m2 increase in BMI on the odds of CHD.

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