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