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Meta-Analysis
. 2015 Apr;44(2):578-86.
doi: 10.1093/ije/dyv094. Epub 2015 May 27.

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

Sara Hägg  1 , Tove Fall  1 , Alexander Ploner  1 , Reedik Mägi  1 , Krista Fischer  1 , Harmen H M Draisma  1 , Mart Kals  1 , Paul S de Vries  1 , Abbas Dehghan  1 , Sara M Willems  1 , Antti-Pekka Sarin  1 , Kati Kristiansson  1 , Marja-Liisa Nuotio  1 , Aki S Havulinna  1 , Renée F A G de Bruijn  1 , M Arfan Ikram  1 , Maris Kuningas  1 , Bruno H Stricker  1 , Oscar H Franco  1 , Beben Benyamin  1 , Christian Gieger  1 , Alistair S Hall  1 , Ville Huikari  1 , Antti Jula  1 , Marjo-Riitta Järvelin  1 , Marika Kaakinen  1 , Jaakko Kaprio  1 , Michael Kobl  1 , Massimo Mangino  1 , Christopher P Nelson  1 , Aarno Palotie  1 , Nilesh J Samani  1 , Tim D Spector  1 , David P Strachan  1 , Martin D Tobin  1 , John B Whitfield  1 , André G Uitterlinden  1 , Veikko Salomaa  1 , Ann-Christine Syvänen  1 , Kari Kuulasmaa  1 , Patrik K Magnusson  1 , Tõnu Esko  1 , Albert Hofman  1 , Eco J C de Geus  1 , Lars Lind  1 , Vilmantas Giedraitis  1 , Markus Perola  1 , Alun Evans  1 , Jean Ferrières  1 , Jarmo Virtamo  1 , Frank Kee  1 , David-Alexandre Tregouet  1 , Dominique Arveiler  1 , Philippe Amouyel  1 , Francesco Gianfagna  1 , Paolo Brambilla  1 , Samuli Ripatti  1 , Cornelia M van Duijn  1 , Andres Metspalu  1 , Inga Prokopenko  1 , Mark I McCarthy  1 , Nancy L Pedersen  1 , Erik Ingelsson  1 ; European Network for Genetic and Genomic Epidemiology Consortium
Affiliations
Meta-Analysis

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

Sara Hägg et al. Int J Epidemiol. 2015 Apr.

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.

Keywords: Cardiovascular disease; Mendelian randomization; body mass index; epidemiology.

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Figures

Figure 1.
Figure 1.
Directed acyclic graph explaining the relationships between exposure (BMI) and outcome (cardiovascular disease) with the genetic instrument (genetic score). The genetic risk score comprising up to 32 BMI-associated SNPs was associated with BMI and further with cardiovascular disease, and a non-confounded instrumental variable (IV) was calculated providing estimates for causal associations between BMI and outcome. Data used for the analyses were primarily ENGAGE cohorts, with sensitivity analyses in TWINGENE, and in addition CARDIoGRAMplusC4D consortium data.
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