Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.

Int J Epidemiol
Authors
Keywords
Abstract

BACKGROUND: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.

METHODS: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22,193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.

RESULTS: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.

CONCLUSIONS: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

Year of Publication
2015
Journal
Int J Epidemiol
Volume
44
Issue
2
Pages
578-86
Date Published
2015 Apr
ISSN
1464-3685
URL
DOI
10.1093/ije/dyv094
PubMed ID
26016847
PubMed Central ID
PMC4553708
Links
Grant list
AG04563 / AG / NIA NIH HHS / United States
G1001799 / Medical Research Council / United Kingdom
NIH, R01D0042157-01A / PHS HHS / United States
G0601463 / Medical Research Council / United Kingdom
N01-RC-45035 / RC / CCR NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
AG10175 / AG / NIA NIH HHS / United States
NIMH U24 MH068457-06 / PHS HHS / United States
AG028555 / AG / NIA NIH HHS / United States
5R01MH63706:02 / MH / NIMH NIH HHS / United States
1RL1MH083268-01 / MH / NIMH NIH HHS / United States
1RC2MH089951-01 / MH / NIMH NIH HHS / United States
MC_UP_0801/1 / Medical Research Council / United Kingdom
G0500539 / Medical Research Council / United Kingdom
1RC2MH089995-01 / MH / NIMH NIH HHS / United States
MR/N01104X/1 / Medical Research Council / United Kingdom
N01-RC-37004 / RC / CCR NIH HHS / United States
N01-CN-45165 / CN / NCI NIH HHS / United States
AG08861 / AG / NIA NIH HHS / United States
AG08724 / AG / NIA NIH HHS / United States
G0902313 / Medical Research Council / United Kingdom
5R01HL087679-02 / HL / NHLBI NIH HHS / United States
098381 / Wellcome Trust / United Kingdom
G1002319 / Medical Research Council / United Kingdom
DK U01-066134 / DK / NIDDK NIH HHS / United States
MR/L01629X/1 / Medical Research Council / United Kingdom
G0600705 / Medical Research Council / United Kingdom
MH081802 / MH / NIMH NIH HHS / United States