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

S. Hägg; T. Fall; A. Ploner; R. Mägi; K. Fischer; H.H.M. Draisma; M. Kals; P.S. de Vries; A. Dehghan; S.M. Willems; A.-P. Sarin; K. Kristiansson; M.L. Nuotio; A.S. Havulinna; R.F.A.G. de Bruijn; M. Arfan Ikram; M. Kuningas; B.H. Stricker; O.H. Franco; B. Benyamin; C. Gieger; A.S. Hall; V. Huikari; A. Jula; M.-R. Jarvelin; M. Kaakinen; J. Kaprio; M. Kobl; M. Mangino; C.P. Nelson; A. Palotie; N.J. Samani; T.D. Spector; D.P. Strachan; M.D. Tobin; J.B. Whitfield; A.G. Uitterlinden; V. Salomaa; A.C. Syvänen; K. Kuulasmaa; P.K. Magnusson; T. Esko; A. Hofman; E.J.C. de Geus; L. Lind; V. Giedraitis; M. Perola; A. Evans; J. Ferrières; J. Virtamo; F Kee; D.A. Tregouet; D. Arveiler; P. Amouyel; F. Gianfagna; P. Brambilla; S. Ripatti; C.M. van Duijn; A. Metspalu; I. Prokopenko; M.I. McCarthy; N.L. Pedersen; E. Ingelsson

doi:10.1093/ije/dyv094

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

S. Hägg, T. Fall, A. Ploner, R. Mägi, K. Fischer, H.H.M. Draisma, M. Kals, P.S. de Vries, A. Dehghan, S.M. Willems, A.-P. Sarin, K. Kristiansson, M.L. Nuotio, A.S. Havulinna, R.F.A.G. de Bruijn, M. Arfan Ikram, M. Kuningas, B.H. Stricker, O.H. Franco, B. BenyaminC. Gieger, A.S. Hall, V. Huikari, A. Jula, M.-R. Jarvelin, M. Kaakinen, J. Kaprio, M. Kobl, M. Mangino, C.P. Nelson, A. Palotie, N.J. Samani, T.D. Spector, D.P. Strachan, M.D. Tobin, J.B. Whitfield, A.G. Uitterlinden, V. Salomaa, A.C. Syvänen, K. Kuulasmaa, P.K. Magnusson, T. Esko, A. Hofman, E.J.C. de Geus, L. Lind, V. Giedraitis, M. Perola, A. Evans, J. Ferrières, J. Virtamo, F Kee, D.A. Tregouet, D. Arveiler, P. Amouyel, F. Gianfagna, P. Brambilla, S. Ripatti, C.M. van Duijn, A. Metspalu, I. Prokopenko, M.I. McCarthy, N.L. Pedersen, E. Ingelsson

Biological Psychology

Research output: Contribution to Journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	578-586
Number of pages	9
Journal	International Journal of Epidemiology
Volume	44
Issue number	2
DOIs	https://doi.org/10.1093/ije/dyv094
Publication status	Published - 2015

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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., Arfan Ikram, M., 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. https://doi.org/10.1093/ije/dyv094

@article{8b08910b32f747d88908b1b0d410c7f2,

title = "Adiposity as a cause of cardiovascular disease: a Mendelian randomization study",

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.",

author = "S. H{\"a}gg and T. Fall and A. Ploner and R. M{\"a}gi and K. Fischer and H.H.M. Draisma and M. Kals and {de Vries}, P.S. and A. Dehghan and S.M. Willems and A.-P. Sarin and K. Kristiansson and M.L. Nuotio and A.S. Havulinna and {de Bruijn}, R.F.A.G. and {Arfan Ikram}, M. and M. Kuningas and B.H. Stricker and O.H. Franco and B. Benyamin and C. Gieger and A.S. Hall and V. Huikari and A. Jula and M.-R. Jarvelin and M. Kaakinen and J. Kaprio and M. Kobl and M. Mangino and C.P. Nelson and A. Palotie and N.J. Samani and T.D. Spector and D.P. Strachan and M.D. Tobin and J.B. Whitfield and A.G. Uitterlinden and V. Salomaa and A.C. Syv{\"a}nen and K. Kuulasmaa and P.K. Magnusson and T. Esko and A. Hofman and {de Geus}, E.J.C. and L. Lind and V. Giedraitis and M. Perola and A. Evans and J. Ferri{\`e}res and J. Virtamo and F Kee and D.A. Tregouet and D. Arveiler and P. Amouyel and F. Gianfagna and P. Brambilla and S. Ripatti and {van Duijn}, C.M. and A. Metspalu and I. Prokopenko and M.I. McCarthy and N.L. Pedersen and E. Ingelsson",

year = "2015",

doi = "10.1093/ije/dyv094",

language = "English",

volume = "44",

pages = "578--586",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "2",

}

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, ML, Havulinna, AS, de Bruijn, RFAG, Arfan Ikram, M, Kuningas, M, Stricker, BH, Franco, OH, Benyamin, B, Gieger, C, Hall, AS, Huikari, V, Jula, A, Jarvelin, 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, AC, 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, DA, Arveiler, D, Amouyel, P, Gianfagna, F, Brambilla, P, Ripatti, S, van Duijn, CM, Metspalu, A, Prokopenko, I, McCarthy, MI, Pedersen, NL & Ingelsson, E 2015, 'Adiposity as a cause of cardiovascular disease: a Mendelian randomization study', International Journal of Epidemiology, vol. 44, no. 2, pp. 578-586. https://doi.org/10.1093/ije/dyv094

TY - JOUR

T1 - Adiposity as a cause of cardiovascular disease: a Mendelian randomization study

AU - Hägg, S.

AU - Fall, T.

AU - Ploner, A.

AU - Mägi, R.

AU - Fischer, K.

AU - Draisma, H.H.M.

AU - Kals, M.

AU - de Vries, P.S.

AU - Dehghan, A.

AU - Willems, S.M.

AU - Sarin, A.-P.

AU - Kristiansson, K.

AU - Nuotio, M.L.

AU - Havulinna, A.S.

AU - de Bruijn, R.F.A.G.

AU - Arfan Ikram, M.

AU - Kuningas, M.

AU - Stricker, B.H.

AU - Franco, O.H.

AU - Benyamin, B.

AU - Gieger, C.

AU - Hall, A.S.

AU - Huikari, V.

AU - Jula, A.

AU - Jarvelin, M.-R.

AU - Kaakinen, M.

AU - Kaprio, J.

AU - Kobl, M.

AU - Mangino, M.

AU - Nelson, C.P.

AU - Palotie, A.

AU - Samani, N.J.

AU - Spector, T.D.

AU - Strachan, D.P.

AU - Tobin, M.D.

AU - Whitfield, J.B.

AU - Uitterlinden, A.G.

AU - Salomaa, V.

AU - Syvänen, A.C.

AU - Kuulasmaa, K.

AU - Magnusson, P.K.

AU - Esko, T.

AU - Hofman, A.

AU - de Geus, E.J.C.

AU - Lind, L.

AU - Giedraitis, V.

AU - Perola, M.

AU - Evans, A.

AU - Ferrières, J.

AU - Virtamo, J.

AU - Kee, F

AU - Tregouet, D.A.

AU - Arveiler, D.

AU - Amouyel, P.

AU - Gianfagna, F.

AU - Brambilla, P.

AU - Ripatti, S.

AU - van Duijn, C.M.

AU - Metspalu, A.

AU - Prokopenko, I.

AU - McCarthy, M.I.

AU - Pedersen, N.L.

AU - Ingelsson, E.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1093/ije/dyv094

DO - 10.1093/ije/dyv094

M3 - Article

VL - 44

SP - 578

EP - 586

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

IS - 2

ER -

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

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