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

Hägg S., Fall T., Ploner A., Mägi R., Fischer K., Draisma HHM., Kals M., de Vries PS., Dehghan A., Willems SM., Sarin A-P., Kristiansson K., Nuotio M-L., Havulinna AS., de Bruijn RFAG., Ikram MA., Kuningas M., Stricker BH., Franco OH., Benyamin B., Gieger C., Hall AS., Huikari V., Jula A., Järvelin M-R., 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 A-C., Kuulasmaa K., Magnusson PK., Esko T., Hofman A., de Geus EJC., Lind L., Giedraitis V., Perola M., Evans A., Ferrières J., Virtamo J., Kee F., Tregouet D-A., 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.

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.

Original publication

DOI

10.1093/ije/dyv094

Type

Journal article

Journal

International journal of epidemiology

Publication Date

04/2015

Volume

44

Pages

578 - 586

Addresses

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, Estonian Genome Center, University of Tartu, Tartu, Estonia, Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands, EMGO Institute for Health and Care Research, Amsterdam, The Netherlands, Institute of Mathematical Statistics, University of Tartu, Tartu, Estonia, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, Leiden, The Netherlands, Department of Genetic Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland, National Institute for Health and Welfare, Helsinki, Finland, Department of Neurology, and Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands, Inspectorate for Health Care, The Hague, The Netherlands, Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia, Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany, Division of Epidemiology, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK, Center for Life Course and Systems Epidemiology, University of Oulu, Oulu, Finland, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland, Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland, MRC Health Protection Agency (HPE) Centre for Environment and Health, Imperial College London, London, UK, Unit of Primary Care, Oulu University Hospital, Oulu, Finland, Hjelt Institute, University of Helsinki,

Keywords

European Network for Genetic and Genomic Epidemiology Consortium, Humans, Cardiovascular Diseases, Body Mass Index, Prospective Studies, Cross-Sectional Studies, Polymorphism, Single Nucleotide, Middle Aged, Female, Male, Adiposity, Mendelian Randomization Analysis