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

Fall, Tove; Hagg, Sara; Maegi, Reedik; Ploner, Alexander; Fischer, Krista; Horikoshi, Momoko; Sarin, Antti-Pekka; Thorleifsson, Gudmar; Ladenvall, Claes LU and Kals, Mart, et al. (2013) In PLoS Medicine 10(6).
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),... (More)
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. (Less)
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PLoS Medicine
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10
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6
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Public Library of Science
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  • wos:000321034800017
  • scopus:84879326263
ISSN
1549-1676
DOI
10.1371/journal.pmed.1001474
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English
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5ad70ca3-e840-4447-88b1-f702fdef0240 (old id 3975210)
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2013-09-02 07:36:22
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2019-03-19 01:28:41
@article{5ad70ca3-e840-4447-88b1-f702fdef0240,
  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&lt;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&lt;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.},
  articleno    = {e1001474},
  author       = {Fall, Tove and Hagg, Sara and Maegi, Reedik and Ploner, Alexander and Fischer, Krista and Horikoshi, Momoko and Sarin, Antti-Pekka and Thorleifsson, Gudmar and Ladenvall, Claes and Kals, Mart and Kuningas, Maris and Draisma, Harmen H. M. and Ried, Janina S. and van Zuydam, Natalie R. and Huikari, Ville and Mangino, Massimo and Sonestedt, Emily and Benyamin, Beben and Nelson, Christopher P. and Rivera, Natalia V. and Kristiansson, Kati and Shen, Huei-yi and Havulinna, Aki S. and Dehghan, Abbas and Donnelly, Louise A. and Kaakinen, Marika and Nuotio, Marja-Liisa and Robertson, Neil and de Bruijn, Renee F. A. G. and Ikram, M. Arfan and Amin, Najaf and Balmforth, Anthony J. and Braund, Peter S. and Doney, Alexander S. F. and Doering, Angela and Elliott, Paul and Esko, Tonu and Franco, Oscar H. and Gretarsdottir, Solveig and Hartikainen, Anna-Liisa and Heikkila, Kauko and Herzig, Karl-Heinz and Holm, Hilma and Hottenga, Jouke Jan and Hypponen, Elina and Illig, Thomas and Isaacs, Aaron and Isomaa, Bo and Karssen, Lennart C. and Kettunen, Johannes and Koenig, Wolfgang and Kuulasmaa, Kari and Laatikainen, Tiina and Laitinen, Jaana and Lindgren, Cecilia and Lyssenko, Valeriya and Laara, Esa and Rayner, Nigel W. and Mannisto, Satu and Pouta, Anneli and Rathmann, Wolfgang and Rivadeneira, Fernando and Ruokonen, Aimo and Savolainen, Markku J. and Sijbrands, Eric J. G. and Small, Kerrin S. and Smit, Jan H. and Steinthorsdottir, Valgerdur and Syvanen, Ann-Christine and Taanila, Anja and Tobin, Martin D. and Uitterlinden, Andre G. and Willems, Sara M. and Willemsen, Gonneke and Witteman, Jacqueline and Perola, Markus and Evans, Alun and Ferrieres, Jean and Virtamo, Jarmo and Kee, Frank and Tregouet, David-Alexandre and Arveiler, Dominique and Amouyel, Philippe and Ferrario, Marco M. and Brambilla, Paolo and Hall, Alistair S. and Heath, AndrewC. and Madden, Pamela A. F. and Martin, Nicholas G. and Montgomery, Grant W. and Whitfield, John B. and Jula, Antti and Knekt, Paul and Oostra, Ben and van Duijn, Cornelia M. and Penninx, Brenda W. J. H. and Smith, George Davey and Kaprio, Jaakko and Samani, Nilesh J. and Gieger, Christian and Peters, Annette and Wichmann, H. -Erich and Boomsma, Dorret I. and de Geus, Eco J. C. and Tuomi, TiinaMaija and Power, Chris and Hammond, Christopher J. and Spector, Tim D. and Lind, Lars and Orho-Melander, Marju and Palmer, Colin Neil Alexander and Morris, Andrew D. and Groop, Leif and Jarvelin, Marjo-Riitta and Salomaa, Veikko and Vartiainen, Erkki and Hofman, Albert and Ripatti, Samuli and Metspalu, Andres and Thorsteinsdottir, Unnur and Stefansson, Kari and Pedersen, Nancy L. and McCarthy, Mark I. and Ingelsson, Erik and Prokopenko, Inga},
  issn         = {1549-1676},
  language     = {eng},
  number       = {6},
  publisher    = {Public Library of Science},
  series       = {PLoS Medicine},
  title        = {The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis},
  url          = {http://dx.doi.org/10.1371/journal.pmed.1001474},
  volume       = {10},
  year         = {2013},
}