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

Author:
  • Tove Fall
  • Sara Hagg
  • Reedik Maegi
  • 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. Rivera
  • Kati Kristiansson
  • Huei-yi Shen
  • Aki S. Havulinna
  • Abbas Dehghan
  • Louise A. Donnelly
  • Marika Kaakinen
  • Marja-Liisa Nuotio
  • Neil Robertson
  • Renee F. A. G. de Bruijn
  • M. Arfan Ikram
  • Najaf Amin
  • Anthony J. Balmforth
  • Peter S. Braund
  • Alexander S. F. Doney
  • Angela Doering
  • Paul Elliott
  • Tonu Esko
  • Oscar H. Franco
  • Solveig Gretarsdottir
  • Anna-Liisa Hartikainen
  • Kauko Heikkila
  • Karl-Heinz Herzig
  • Hilma Holm
  • Jouke Jan Hottenga
  • Elina Hypponen
  • Thomas Illig
  • Aaron Isaacs
  • Bo Isomaa
  • Lennart C. Karssen
  • Johannes Kettunen
  • Wolfgang Koenig
  • Kari Kuulasmaa
  • Tiina Laatikainen
  • Jaana Laitinen
  • Cecilia Lindgren
  • Valeriya Lyssenko
  • Esa Laara
  • Nigel W. Rayner
  • Satu Mannisto
  • 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 Syvanen
  • Anja Taanila
  • Martin D. Tobin
  • Andre G. Uitterlinden
  • Sara M. Willems
  • Gonneke Willemsen
  • Jacqueline Witteman
  • Markus Perola
  • Alun Evans
  • Jean Ferrieres
  • Jarmo Virtamo
  • Frank Kee
  • David-Alexandre Tregouet
  • Dominique Arveiler
  • Philippe Amouyel
  • Marco M. Ferrario
  • Paolo Brambilla
  • Alistair S. Hall
  • AndrewC. 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
  • TiinaMaija 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 Jarvelin
  • Veikko Salomaa
  • Erkki Vartiainen
  • Albert Hofman
  • Samuli Ripatti
  • Andres Metspalu
  • Unnur Thorsteinsdottir
  • Kari Stefansson
  • Nancy L. Pedersen
  • Mark I. McCarthy
  • Erik Ingelsson
  • Inga Prokopenko
Publishing year: 2013
Language: English
Publication/Series: PLoS Medicine
Volume: 10
Issue: 6
Document type: Journal article
Publisher: Public Library of Science

Abstract english

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.

Keywords

  • Nutrition and Dietetics
  • Endocrinology and Diabetes

Other

Published
  • Genomics, Diabetes and Endocrinology
  • Nutrition Epidemiology
  • ISSN: 1549-1676
Emily Sonestedt
E-mail: emily [dot] sonestedt [at] med [dot] lu [dot] se

Associate senior lecturer

Nutrition Epidemiology

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Jan Waldenströms gata 35, CRC 60:13, Malmö

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