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

Sara Hägg; Tove Fall; Alexander Ploner; Reedik Mägi; Krista Fischer; Harmen HM Draisma; Mart Kals; Paul S. de Vries; Abbas Dehghan; Sara M. Willems; Antti-Pekka Sarin; Kati  Kristiansson; Marja-Liisa Nuotio; Aki S Havulinna; Renee  FAG de Bruijn; M. Arfan Ikram; Maris Kuningas; Bruno H. Stricker; Oscar H. Franco; Beben Benyamin; Christian Gieger; Alistair S. Hall; Ville Huikari; Antti Jula; Marjo-Riitta Jarvelin; 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; Andre G. Uitterlinden; Veikko Salomaa; Ann-Christine Syvänen; Kari Kuulasmaa; Patrik K. Magnusson; Tonu Esko; Albert Hofman; Eco J.C. de Geus; Lars Lind; Vilmantas Giedraitis; Markus Perola; Alun Evans; Jean Ferrieres; 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

doi:10.1093/ije/dyv094

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

Sara Hägg, Tove Fall, Alexander Ploner, Reedik Mägi, Krista Fischer, Harmen HM Draisma, Mart Kals, Paul S. de Vries, Abbas Dehghan, Sara M. Willems, Antti-Pekka Sarin, Kati Kristiansson, Marja-Liisa Nuotio, Aki S Havulinna, Renee FAG 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 Jarvelin, 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, Andre G. Uitterlinden, Veikko Salomaa, Ann-Christine Syvänen, Kari Kuulasmaa, Patrik K. Magnusson, Tonu Esko, Albert Hofman, Eco J.C. de Geus, Lars Lind, Vilmantas Giedraitis, Markus Perola, Alun Evans, Jean Ferrieres, 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

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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
Early online date	27 May 2015
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. HM., Kals, M., de Vries, P. S., Dehghan, A., Willems, S. M., Sarin, A.-P., Kristiansson, K., Nuotio, M.-L., Havulinna, A. S., FAG de Bruijn, R., 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. https://doi.org/10.1093/ije/dyv094

@article{542e81b389bd4ba6a61c8bc9adfea813,

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 = "Sara H{\"a}gg and Tove Fall and Alexander Ploner and Reedik M{\"a}gi and Krista Fischer and Draisma, {Harmen HM} and Mart Kals and {de Vries}, {Paul S.} and Abbas Dehghan and Willems, {Sara M.} and Antti-Pekka Sarin and Kati Kristiansson and Marja-Liisa Nuotio and Havulinna, {Aki S} and {FAG de Bruijn}, Renee and Ikram, {M. Arfan} and Maris Kuningas and Stricker, {Bruno H.} and Franco, {Oscar H.} and Beben Benyamin and Christian Gieger and Hall, {Alistair S.} and Ville Huikari and Antti Jula and Marjo-Riitta Jarvelin and Marika Kaakinen and Jaakko Kaprio and Michael Kobl and Massimo Mangino and Nelson, {Christopher P.} and Aarno Palotie and Samani, {Nilesh J.} and Spector, {Tim D.} and Strachan, {David P.} and Tobin, {Martin D.} and Whitfield, {John B.} and Uitterlinden, {Andre G.} and Veikko Salomaa and Ann-Christine Syv{\"a}nen and Kari Kuulasmaa and Magnusson, {Patrik K.} and Tonu Esko and Albert Hofman and {de Geus}, {Eco J.C.} and Lars Lind and Vilmantas Giedraitis and Markus Perola and Alun Evans and Jean Ferrieres and Jarmo Virtamo and Frank Kee and David-Alexandre Tregouet and Dominique Arveiler and Philippe Amouyel and Francesco Gianfagna and Paolo Brambilla and Samuli Ripatti and {van Duijn}, {Cornelia M.} and Andres Metspalu and Inga Prokopenko and McCarthy, {Mark I.} and Pedersen, {Nancy L.} and Erik 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, M-L, Havulinna, AS, FAG de Bruijn, R, Ikram, MA, 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, A-C, Kuulasmaa, K, Magnusson, PK, Esko, T, Hofman, A, de Geus, EJC, Lind, L, Giedraitis, V, Perola, M, Evans, A, Ferrieres, 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 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, Sara

AU - Fall, Tove

AU - Ploner, Alexander

AU - Mägi, Reedik

AU - Fischer, Krista

AU - Draisma, Harmen HM

AU - Kals, Mart

AU - de Vries, Paul S.

AU - Dehghan, Abbas

AU - Willems, Sara M.

AU - Sarin, Antti-Pekka

AU - Kristiansson, Kati

AU - Nuotio, Marja-Liisa

AU - Havulinna, Aki S

AU - FAG de Bruijn, Renee

AU - Ikram, M. Arfan

AU - Kuningas, Maris

AU - Stricker, Bruno H.

AU - Franco, Oscar H.

AU - Benyamin, Beben

AU - Gieger, Christian

AU - Hall, Alistair S.

AU - Huikari, Ville

AU - Jula, Antti

AU - Jarvelin, Marjo-Riitta

AU - Kaakinen, Marika

AU - Kaprio, Jaakko

AU - Kobl, Michael

AU - Mangino, Massimo

AU - Nelson, Christopher P.

AU - Palotie, Aarno

AU - Samani, Nilesh J.

AU - Spector, Tim D.

AU - Strachan, David P.

AU - Tobin, Martin D.

AU - Whitfield, John B.

AU - Uitterlinden, Andre G.

AU - Salomaa, Veikko

AU - Syvänen, Ann-Christine

AU - Kuulasmaa, Kari

AU - Magnusson, Patrik K.

AU - Esko, Tonu

AU - Hofman, Albert

AU - de Geus, Eco J.C.

AU - Lind, Lars

AU - Giedraitis, Vilmantas

AU - Perola, Markus

AU - Evans, Alun

AU - Ferrieres, Jean

AU - Virtamo, Jarmo

AU - Kee, Frank

AU - Tregouet, David-Alexandre

AU - Arveiler, Dominique

AU - Amouyel, Philippe

AU - Gianfagna, Francesco

AU - Brambilla, Paolo

AU - Ripatti, Samuli

AU - van Duijn, Cornelia M.

AU - Metspalu, Andres

AU - Prokopenko, Inga

AU - McCarthy, Mark I.

AU - Pedersen, Nancy L.

AU - Ingelsson, Erik

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

SN - 0300-5771

VL - 44

SP - 578

EP - 586

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 2

ER -

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

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