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

• Published in: International journal of epidemiology Vol. 44; no. 2; pp. 578 - 586
• Main Authors: Hägg, Sara, Fall, Tove, Ploner, Alexander, Mägi, Reedik, Fischer, Krista, Draisma, Harmen H M, Kals, Mart, de Vries, Paul S, Dehghan, Abbas, Willems, Sara M, Sarin, Antti-Pekka, Kristiansson, Kati, Nuotio, Marja-Liisa, Havulinna, Aki S, de Bruijn, Renée F A G, Ikram, M Arfan, Kuningas, Maris, Stricker, Bruno H, Franco, Oscar H, Benyamin, Beben, Gieger, Christian, Hall, Alistair S, Huikari, Ville, Jula, Antti, Järvelin, Marjo-Riitta, Kaakinen, Marika, Kaprio, Jaakko, Kobl, Michael, Mangino, Massimo, Nelson, Christopher P, Palotie, Aarno, Samani, Nilesh J, Spector, Tim D, Strachan, David P, Tobin, Martin D, Whitfield, John B, Uitterlinden, André G, Salomaa, Veikko, Syvänen, Ann-Christine, Kuulasmaa, Kari, Magnusson, Patrik K, Esko, Tõnu, Hofman, Albert, de Geus, Eco J C, Lind, Lars, Giedraitis, Vilmantas, Perola, Markus, Evans, Alun, Ferrières, Jean, Virtamo, Jarmo, Kee, Frank, Tregouet, David-Alexandre, Arveiler, Dominique, Amouyel, Philippe, Gianfagna, Francesco, Brambilla, Paolo, Ripatti, Samuli, van Duijn, Cornelia M, Metspalu, Andres, Prokopenko, Inga, McCarthy, Mark I, Pedersen, Nancy L, Ingelsson, Erik
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2015
• Subjects: Adiposity - genetics; Body Mass Index; Cardiovascular disease; Cardiovascular Diseases - genetics; Cross-Sectional Studies; epidemiology; Female; Humans; Male; Medicin och hälsovetenskap; Mendelian randomization; Mendelian Randomization Analysis; Mendelian Randomization Causal Analysis; Middle Aged; Polymorphism, Single Nucleotide - genetics; Prospective Studies; epidemiology; Cardiovascular disease; Mendelian randomization; body mass index
• ISSN: 0300-5771; 1464-3685; 1464-3685
• DOI: 10.1093/ije/dyv094

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