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

Date Published: January 3, 2019

Publisher: Public Library of Science

Author(s): Mattias Johansson, Robert Carreras-Torres, 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, Vladimir Janout, Dana Mates, Anush Mukeriya, 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, Cosetta Minelli

Abstract: BackgroundSeveral 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 findingsGenetic 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.ConclusionsThis study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Partial Text: The etiology of renal cell carcinoma (RCC) is only partly understood [1]. An increased risk of RCC has been observed for individuals with high body mass index (BMI), elevated blood pressure, and triglycerides [2]. However, these obesity-related exposures are inherently interrelated, and traditional epidemiological studies have not been able to untangle which individual factors directly influence RCC risk and which are merely correlated with the underlying causal factor.

This MR analysis confirmed a role for higher BMI and DBP in RCC etiology and provided novel evidence for a role of fasting insulin. In contrast, we found little evidence for a role of other obesity-related risk factors RCC etiology, with evaluated risk factors including diagnosis of type 2 diabetes, SBP, and blood lipid levels.



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