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

Mattias Johansson (1) , Robert Carreras-Torres (1) , Ghislaine Scelo (1) , Mark P Purdue (2) , Daniela Mariosa (1) , David C Muller (3) , Nicolas J Timpson (4) , Philip C Haycock (4) , Kevin M Brown (2) , Zhaoming Wang (5) , Yuanqing Ye (6) , Jonathan N Hofmann (2) , Matthieu Foll (1) , Valerie Gaborieau (1) , Mitchell J Machiela (2) , Leandro M Colli (2) , Peng Li , Jean-Guillaume Garnier (7, 8) , Helene Blanche (9) , Anne Boland (7, 10) , Laurie Burdette (2) , Egor Prokhortchouk (11) , Konstantin G Skryabin (11) , Meredith Yeager (2) , Sanja Radojevic-Skodric (12) , Simona Ognjanovic (13) , Lenka Foretova (14) , Ivana Holcatova (15) , Vladimir Janout (16) , Dana Mates (17) , Anush Mukeriya (18, 19) , Stefan Rascu (20) , David Zaridze (18, 19) , Vladimir Bencko (21) , Cezary Cybulski (22) , Eleonora Fabianova , Viorel Jinga (20) , Jolanta Lissowska (23) , Jan Lubinski (22) , Marie Navratilova (14) , Peter Rudnai (24) , Simone Benhamou (25, 26) , Geraldine Cancel-Tassin (27, 28) , Olivier Cussenot (27, 28) , Elisabete Weiderpass (29) , Börje Ljungberg (30) , Raviprakash Tumkur Sitaram , Christel Häggström (30) , Fiona Bruinsma , Susan J Jordan (31) , Gianluca Severi (32, 33) , Ingrid Winship , Kristian Hveem (34) , Lars J Vatten (34) , Tony Fletcher (35) , Susanna C Larsson (36, 37) , Alicja Wolk (36, 37) , 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 (7, 8) , Marc Gunter (1) , James D Mckay , Xifeng Wu , Richard S Houlston , Stephen J Chanock , Caroline Relton , J. Brent Richards , Richard M Martin , George Davey Smith , Paul Brennan (1)

1 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
2 NCI-NIH - National Cancer Institute [Bethesda]
3 Imperial College London
4 University of Bristol [Bristol]
5 St Jude Children's Research Hospital
6 The University of Texas M.D. Anderson Cancer Center [Houston]
7 CNG - Centre National de Génotypage
8 CEPH - Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris]
9 Fondation Jean Dausset CEPH
10 JACOB - Institut de Biologie François JACOB
11 RAS - Russian Academy of Sciences [Moscow]
12 KCS - Clinical Center of Serbia
13 Mayo Clinic [Rochester]
14 MMCI - Masaryk Memorial Cancer Institute
15 Medicine Charles University and General Faculty Hospital in Prague
16 Palacky University Olomouc
17 INSP - National Institute of Public Health [Romania]
18 N.N. Blokhin National Medical Research Center of Oncology
19 Russian Cancer Research Centre
20 UMPCD - University of Medicine and Pharmacy “Carol Davila” Bucharest
21 Institute of Hygiene and Epidemiology
22 Department of Genetics and Pathology
23 The M Sklodowska-Curie Cancer Center and Institute of Oncology
24 National center for public health [Hungary]
25 U946 - Variabilité Génétique et Maladies Humaines
26 CNRS UMR 8200 - Réparation de l’ADN
27 CeRePP - Centre de Recherche pour les Pathologies Prostatiques [Paris]
28 IUC - Institut Universitaire de Cancérologie [Sorbonne Université]
29 Cancer Registry of Norway
30 Umeå University, Sweden
31 QIMR Berghofer Medical Research Institute
32 CESP - INSERM U1018 - Equipe 7 - Sexualité et soins (Genre, Sexualité, Santé)
33 HuGeF - Human Genetics Foundation
34 NTNU - Norwegian University of Science and Technology [Trondheim]
35 LSHTM - London School of Hygiene and Tropical Medicine
36 Karolinska Institutet [Stockholm]
37 Uppsala University

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.

Domaines: Sciences du Vivant [q-bio]; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Cancer

Mattias Johansson, Robert Carreras-Torres, Ghislaine Scelo, Mark P Purdue, Daniela Mariosa, et al.. The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study. PLoS Medicine, 2019, 16 (1), pp.e1002724. ⟨10.1371/journal.pmed.1002724⟩. ⟨cea-04430719⟩