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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numberdyv094
Pages (from-to)578-586
Number of pages9
JournalInternational Journal of Epidemiology
Volume44
Issue number2
DOIs
Publication statusPublished - May 27 2015

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Keywords

  • Body mass index
  • Cardiovascular disease
  • Epidemiology
  • Mendelian randomization

ASJC Scopus subject areas

  • Epidemiology

Cite this

Hägg, S., Fall, T., Ploner, A., Mägi, R., Fischer, K., Draisma, H. H. M., Kals, M., De Vries, P. S., Dehghan, A., Willems, S. M., Sarin, A. P., Kristiansson, K., Nuotio, M. L., Havulinna, A. S., De Bruijn, R. F. A. G., Ikram, M. A., Kuningas, M., Stricker, B. H., Franco, O. H., ... Ingelsson, E. (2015). Adiposity as a cause of cardiovascular disease: A Mendelian randomization study. International Journal of Epidemiology, 44(2), 578-586. [dyv094]. https://doi.org/10.1093/ije/dyv094