The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study

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The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
Journal Title:
PLOS Medicine
Mattias Johansson, Robert Carreras-Torres, Vladimir Janout, Dana Mates, Anush Mukeriya, Ghislaine Scelo, Mark P. Purdue, Daniela Mariosa, David C. Muller, Nicolas J. Timpson, Philip C. Haycock, Kevin M. Brown, Zhaoming Wang, Yuanqing Ye, Jonathan N. Hofmann, Matthieu Foll, Valerie Gaborieau, Mitchell J. Machiela, Leandro M. Colli, Peng Li, Jean-Guillaume Garnier, Helene Blanche, Anne Boland, Laurie Burdette, Egor Prokhortchouk, Konstantin G. Skryabin, Meredith Yeager, Sanja Radojevic-Skodric, Simona Ognjanovic, Lenka Foretova, Ivana Holcatova, Stefan Rascu, David Zaridze, Vladimir Bencko, Cezary Cybulski, Eleonora Fabianova, Viorel Jinga, Jolanta Lissowska, Jan Lubinski, Marie Navratilova, Peter Rudnai, Simone Benhamou, Geraldine Cancel-Tassin, Olivier Cussenot, Elisabete Weiderpass, Börje Ljungberg, Raviprakash Tumkur Sitaram, Christel Häggström, Fiona Bruinsma, Susan J. Jordan, Gianluca Severi, Ingrid Winship, Kristian Hveem, Lars J. Vatten, Tony Fletcher, Susanna C. Larsson, Alicja Wolk, Rosamonde E. Banks, Peter J. Selby, Douglas F. Easton, Gabriella Andreotti, Laura E. Beane Freeman, Stella Koutros, Satu Männistö, Stephanie Weinstein, Peter E. Clark, Todd L. Edwards, Loren Lipworth, Susan M. Gapstur, Victoria L. Stevens, Hallie Carol, Matthew L. Freedman, Mark M. Pomerantz, Eunyoung Cho, Kathryn M. Wilson, J. Michael Gaziano, Howard D. Sesso, Neal D. Freedman, Alexander S. Parker, Jeanette E. Eckel-Passow, Wen-Yi Huang, Richard J. Kahnoski, Brian R. Lane, Sabrina L. Noyes, David Petillo, Bin Tean Teh, Ulrike Peters, Emily White, Garnet L. Anderson, Lisa Johnson, Juhua Luo, Julie Buring, I-Min Lee, Wong-Ho Chow, Lee E. Moore, Timothy Eisen, Marc Henrion, James Larkin, Poulami Barman, Bradley C. Leibovich, Toni K. Choueiri, G. Mark Lathrop, Jean-Francois Deleuze, Marc Gunter, James D. McKay, Xifeng Wu, Richard S. Houlston, Stephen J. Chanock, Caroline Relton, J. Brent Richards, Richard M. Martin, George Davey Smith, Paul Brennan
Publication Date:
03 January 2019
Article Source: The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study Johansson M, Carreras-Torres R, Scelo G, Purdue MP, Mariosa D, et al. (2019) The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study. PLOS Medicine 16(1): e1002724.
Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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Funding Info:
Funding: This analysis was supported by the World Cancer Research Fund International— (2014/1193, to MJ) and Cancer Research UK— (C18281/A19169, to RMM and CR). Funding for the genome-wide genotyping was provided by the US National Institutes of Health (NIH), National Cancer Institute— (U01CA155309) for those studies coordinated by IARC, and by the intramural research program of the National Cancer Institute, US NIH, for those studies coordinated by the NCI; and the MD Anderson GWAS was supported in part by the NIH (grant R01 CA170298) and the Center for Translational and Public Health Genomics, Duncan Family Institute for Cancer Prevention and Risk Assessment, The University of Texas MD Anderson Cancer Center. RMM is supported by the National Institute for Health Research (NIHR) Bristol Nutritional Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. RCT, PCH, CR, RMM, GDS, MJ, and PB are investigators or researchers on a Cancer Research UK (C18281/A19169) Programme Grant (the Integrative Cancer Epidemiology Programme). CR, GDS, and NT work within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1, MC_UU_12013/2, MC_UU_12013/3). JBR is supported by the Canadian Institutes of Health Research and the Fonds du Recherche Québec-Santé. JL is supported by the RM/ICR NIHR Biomedical Research Centre for Cancer. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. The authors thank all of the participants who took part in this research and the funders and support staff who made this study possible. We further thank Paul Pharoah for his valuable contribution to the study.
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