Adiposity as a cause of cardiovascular disease: a Mendelian randomization study.
Hägg S., Fall T., Ploner A., Mägi R., Fischer K., Draisma HH., Kals M., de Vries PS., Dehghan A., Willems SM., Sarin AP., Kristiansson K., Nuotio ML., Havulinna AS., de Bruijn RF., Ikram MA., Kuningas M., Stricker BH., Franco OH., Benyamin B., Gieger C., Hall AS., Huikari V., Jula A., Järvelin MR., Kaakinen M., Kaprio J., Kobl M., Mangino M., Nelson CP., Palotie A., Samani NJ., Spector TD., Strachan DP., Tobin MD., Whitfield JB., Uitterlinden AG., Salomaa V., Syvänen AC., Kuulasmaa K., Magnusson PK., Esko T., Hofman A., de Geus EJ., Lind L., Giedraitis V., Perola M., Evans A., Ferrières J., Virtamo J., Kee F., Tregouet DA., Arveiler D., Amouyel P., Gianfagna F., Brambilla P., Ripatti S., van Duijn CM., Metspalu A., Prokopenko I., McCarthy MI., Pedersen NL., Ingelsson E., European Network for Genetic and Genomic Epidemiology Consortium None.
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.