@article{10.1371/journal.pmed.1002724, doi = {10.1371/journal.pmed.1002724}, author = {Johansson, Mattias AND Carreras-Torres, Robert AND Scelo, Ghislaine AND Purdue, Mark P. AND Mariosa, Daniela AND Muller, David C. AND Timpson, Nicolas J. AND Haycock, Philip C. AND Brown, Kevin M. AND Wang, Zhaoming AND Ye, Yuanqing AND Hofmann, Jonathan N. AND Foll, Matthieu AND Gaborieau, Valerie AND Machiela, Mitchell J. AND Colli, Leandro M. AND Li, Peng AND Garnier, Jean-Guillaume AND Blanche, Helene AND Boland, Anne AND Burdette, Laurie AND Prokhortchouk, Egor AND Skryabin, Konstantin G. AND Yeager, Meredith AND Radojevic-Skodric, Sanja AND Ognjanovic, Simona AND Foretova, Lenka AND Holcatova, Ivana AND Janout, Vladimir AND Mates, Dana AND Mukeriya, Anush AND Rascu, Stefan AND Zaridze, David AND Bencko, Vladimir AND Cybulski, Cezary AND Fabianova, Eleonora AND Jinga, Viorel AND Lissowska, Jolanta AND Lubinski, Jan AND Navratilova, Marie AND Rudnai, Peter AND Benhamou, Simone AND Cancel-Tassin, Geraldine AND Cussenot, Olivier AND Weiderpass, Elisabete AND Ljungberg, Börje AND Tumkur Sitaram, Raviprakash AND Häggström, Christel AND Bruinsma, Fiona AND Jordan, Susan J. AND Severi, Gianluca AND Winship, Ingrid AND Hveem, Kristian AND Vatten, Lars J. AND Fletcher, Tony AND Larsson, Susanna C. AND Wolk, Alicja AND Banks, Rosamonde E. AND Selby, Peter J. AND Easton, Douglas F. AND Andreotti, Gabriella AND Beane Freeman, Laura E. AND Koutros, Stella AND Männistö, Satu AND Weinstein, Stephanie AND Clark, Peter E. AND Edwards, Todd L. AND Lipworth, Loren AND Gapstur, Susan M. AND Stevens, Victoria L. AND Carol, Hallie AND Freedman, Matthew L. AND Pomerantz, Mark M. AND Cho, Eunyoung AND Wilson, Kathryn M. AND Gaziano, J. Michael AND Sesso, Howard D. AND Freedman, Neal D. AND Parker, Alexander S. AND Eckel-Passow, Jeanette E. AND Huang, Wen-Yi AND Kahnoski, Richard J. AND Lane, Brian R. AND Noyes, Sabrina L. AND Petillo, David AND Teh, Bin Tean AND Peters, Ulrike AND White, Emily AND Anderson, Garnet L. AND Johnson, Lisa AND Luo, Juhua AND Buring, Julie AND Lee, I-Min AND Chow, Wong-Ho AND Moore, Lee E. AND Eisen, Timothy AND Henrion, Marc AND Larkin, James AND Barman, Poulami AND Leibovich, Bradley C. AND Choueiri, Toni K. AND Lathrop, G. Mark AND Deleuze, Jean-Francois AND Gunter, Marc AND McKay, James D. AND Wu, Xifeng AND Houlston, Richard S. AND Chanock, Stephen J. AND Relton, Caroline AND Richards, J. Brent AND Martin, Richard M. AND Davey Smith, George AND Brennan, Paul}, journal = {PLOS Medicine}, publisher = {Public Library of Science}, title = {The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study}, year = {2019}, month = {01}, volume = {16}, url = {https://doi.org/10.1371/journal.pmed.1002724}, pages = {1-16}, abstract = {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.}, number = {1}, }