The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Tove Fall, Sara Hägg, Reedik Mägi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H.M. Draisma, Janina S. Ried, Natalie R. van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P. Nelson, Natalia V. RiveraKati Kristiansson, Huei yi Shen, Aki S. Havulinna, Abbas Dehghan, Louise A. Donnelly, Marika Kaakinen, Marja Liisa Nuotio, Neil Robertson, Renée F.A.G. de Bruijn, M. Arfan Ikram, Najaf Amin, Anthony J. Balmforth, Peter S. Braund, Alexander S.F. Doney, Angela Döring, Paul Elliott, Tõnu Esko, Oscar H. Franco, Solveig Gretarsdottir, Anna Liisa Hartikainen, Kauko Heikkilä, Karl Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Lennart C. Karssen, Johannes Kettunen, Wolfgang Koenig, Kari Kuulasmaa, Tiina Laatikainen, Jaana Laitinen, Cecilia Lindgren, Valeriya Lyssenko, Esa Läärä, Nigel W. Rayner, Satu Männistö, Anneli Pouta, Wolfgang Rathmann, Fernando Rivadeneira, Aimo Ruokonen, Markku J. Savolainen, Eric J.G. Sijbrands, Kerrin S. Small, Jan H. Smit, Valgerdur Steinthorsdottir, Ann Christine Syvänen, Anja Taanila, Martin D. Tobin, Andre G. Uitterlinden, Sara M. Willems, Gonneke Willemsen, Jacqueline Witteman, Markus Perola, Alun Evans, Jean Ferrières, Jarmo Virtamo, Frank Kee, David Alexandre Tregouet, Dominique Arveiler, Philippe Amouyel, Marco M. Ferrario, Paolo Brambilla, Alistair S. Hall, Andrew C. Heath, Pamela A.F. Madden, Nicholas G. Martin, Grant W. Montgomery, John B. Whitfield, Antti Jula, Paul Knekt, Ben Oostra, Cornelia M. van Duijn, Brenda W.J.H. Penninx, George Davey Smith, Jaakko Kaprio, Nilesh J. Samani, Christian Gieger, Annette Peters, H. Erich Wichmann, Dorret I. Boomsma, Eco J.C. de Geus, Tiina Maija Tuomi, Chris Power, Christopher J. Hammond, Tim D. Spector, Lars Lind, Marju Orho-Melander, Colin Neil Alexander Palmer, Andrew D. Morris, Leif Groop, Marjo Riitta Järvelin, Veikko Salomaa, Erkki Vartiainen, Albert Hofman, Samuli Ripatti, Andres Metspalu, Unnur Thorsteinsdottir, Kari Stefansson, Nancy L. Pedersen, Mark I. McCarthy, Erik Ingelsson, Inga Prokopenko

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170 Scopus citations

Abstract

Background:The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.Methods and Findings:We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).Conclusions:We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.Please see later in the article for the Editors' Summary.

Original languageEnglish
Article numbere1001474
JournalPLoS medicine
Volume10
Issue number6
DOIs
StatePublished - Jun 2013

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