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Epidemiology and Genomics Research Program

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

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30605491
PMC6317776
PLoS medicine
Jan. 1, 2019
Mattias Johansson53, Robert Carreras-Torres53, Ghislaine Scelo53, Mark P Purdue38, Daniela Mariosa53, David C Muller47, Nicolas J Timpson61, Philip C Haycock61, Kevin M Brown38, Zhaoming Wang77, Yuanqing Ye20, Jonathan N Hofmann38, Matthieu Foll53, Valerie Gaborieau53, Mitchell J Machiela38, Leandro M Colli38, Peng Li53 62, Jean-Guillaume Garnier12 41, Helene Blanche41, Anne Boland12, Laurie Burdette38, Egor Prokhortchouk40, Konstantin G Skryabin57 40, Meredith Yeager38, Sanja Radojevic-Skodric51 13, Simona Ognjanovic63 55, Lenka Foretova17, Ivana Holcatova52, Vladimir Janout28, Dana Mates67, Anush Mukeriya73, Stefan Rascu10, David Zaridze73, Vladimir Bencko49, Cezary Cybulski54, Eleonora Fabianova71, Viorel Jinga10, Jolanta Lissowska79, Jan Lubinski54, Marie Navratilova17, Peter Rudnai68, Simone Benhamou46 6, Geraldine Cancel-Tassin11 80, Olivier Cussenot11 80 2, Elisabete Weiderpass23 18 31 43, Börje Ljungberg33, Raviprakash Tumkur Sitaram33, Christel Häggström32 16, Fiona Bruinsma7, Susan J Jordan70 74, Gianluca Severi1 45, Ingrid Winship26, Kristian Hveem56, Lars J Vatten29, Tony Fletcher60, Susanna C Larsson48, Alicja Wolk48, Rosamonde E Banks59, Peter J Selby65, Douglas F Easton27 30, Gabriella Andreotti38, Laura E Beane Freeman38, Stella Koutros38, Satu Männistö66, Stephanie Weinstein38, Peter E Clark84, Todd L Edwards25, Loren Lipworth84, Susan M Gapstur3, Victoria L Stevens3, Hallie Carol15, Matthew L Freedman15, Mark M Pomerantz15, Eunyoung Cho5, Kathryn M Wilson44, J Michael Gaziano4, Howard D Sesso44 24, Neal D Freedman38, Alexander S Parker22, Jeanette E Eckel-Passow21, Wen-Yi Huang38, Richard J Kahnoski39, Brian R Lane39 14, Sabrina L Noyes83 76, David Petillo83 37, Bin Tean Teh83 69 50 58 9, Ulrike Peters8, Emily White8, Garnet L Anderson85, Lisa Johnson42, Juhua Luo19, Julie Buring4 24, I-Min Lee4 24, Wong-Ho Chow20, Lee E Moore38, Timothy Eisen82, Marc Henrion78 36, James Larkin72, Poulami Barman21, Bradley C Leibovich34, Toni K Choueiri15, G Mark Lathrop64, Jean-Francois Deleuze12 41, Marc Gunter53, James D McKay53, Xifeng Wu20, Richard S Houlston78, Stephen J Chanock38, Caroline Relton61 75, J Brent Richards35, Richard M Martin61 75 81, George Davey Smith61 75, Paul Brennan53
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  • 1
    "Health across generations" team, CESP Inserm, Facultés de Médicine Université Paris-Sud, UVSQ, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
  • 2
    AP-HP, Department of Urology, Hopitaux Universitaires Est Parisien Tenon, Paris, France.
  • 3
    American Cancer Society, Atlanta, Georgia, United States of America.
  • 4
    Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
  • 5
    Brown University, Providence, Rhode Island, United States of America.
  • 6
    CNRS UMR8200, Institute Gustave Roussy, Villejuif, France.
  • 7
    Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
  • 8
    Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • 9
    Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 10
    Carol Davila University of Medicine and Pharmacy, Th. Burghele Hospital, Bucharest, Romania.
  • 11
    CeRePP, Paris, France.
  • 12
    Centre National de Genotypage, Institut de Genomique, Centre de l'Energie Atomique et aux Energies Alternatives, Evry, France.
  • 13
    Clinic of Urology, Clinical Center of Serbia, Belgrade, Serbia.
  • 14
    College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America.
  • 15
    Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 16
    Department of Biobank Research, Umeå University, Umeå, Sweden.
  • 17
    Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
  • 18
    Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
  • 19
    Department of Epidemiology and Biostatistics, School of Public Health Indiana University Bloomington, Bloomington, Indiana, United States of America.
  • 20
    Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
  • 21
    Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.
  • 22
    Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida, United States of America.
  • 23
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • 24
    Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
  • 25
    Department of Medicine, Division of Epidemiology, Vanderbilt-Ingram Cancer Center, Vanderbilt Genetics Institute, Nashville, Tennessee, United States of America.
  • 26
    Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.
  • 27
    Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
  • 28
    Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic.
  • 29
    Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 30
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
  • 31
    Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
  • 32
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
  • 33
    Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
  • 34
    Department of Urology, Mayo Clinic, Rochester, Minnesota, United States of America.
  • 35
    Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
  • 36
    Dept. of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
  • 37
    Diagnostics Program at Ferris State University, Grand Rapids, Michigan, United States of America.
  • 38
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, Maryland, United States of America.
  • 39
    Division of Urology, Spectrum Health, Grand Rapids, Michigan, United States of America.
  • 40
    Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences, Moscow, Russian Federation.
  • 41
    Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, Paris, France.
  • 42
    Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • 43
    Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
  • 44
    Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
  • 45
    Human Genetics Foundation (HuGeF), Torino, Italy.
  • 46
    INSERM U946, Paris, France.
  • 47
    Imperial College, London, United Kingdom.
  • 48
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 49
    Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 50
    Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
  • 51
    Institute of Pathology, Medical School of Belgrade, Belgrade, Serbia.
  • 52
    Institute of Public Health and Preventive Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 53
    International Agency for Research on Cancer (IARC), Lyon, France.
  • 54
    International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
  • 55
    International Organization for Cancer Prevention and Research (IOCPR), Belgrade, Serbia.
  • 56
    K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
  • 57
    Kurchatov Scientific Center, Moscow, Russian Federation.
  • 58
    Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
  • 59
    Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
  • 60
    London School of Hygiene and Tropical Medicine, University of London, London, United Kingdom.
  • 61
    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
  • 62
    Max Planck Institute for Demographic Research, Rostock, Germany.
  • 63
    Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota, United States of America.
  • 64
    McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
  • 65
    National Institute for Health Research Diagnostic Evidence Cooperative, Division of Surgery, Imperial College London, St Mary's Hospital, London, United Kingdom.
  • 66
    National Institute for Health and Welfare, Helsinki, Finland.
  • 67
    National Institute of Public Health, Bucharest, Romania.
  • 68
    National Public Health Center, National Directorate of Environmental Health, Budapest, Hungary.
  • 69
    Program in Cancer and Stem Cell Biology, Duke-National, University of Singapore Medical School, Singapore, Singapore.
  • 70
    QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
  • 71
    Regional Authority of Public Health in Banska Bystrica, Banska Bystrica, Slovakia.
  • 72
    Royal Marsden NHS Foundation Trust, London, United Kingdom.
  • 73
    Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation.
  • 74
    School of Public Health, The University of Queensland, Brisbane, Australia.
  • 75
    School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
  • 76
    Spectrum Health, Grand Rapids, Michigan, United States of America.
  • 77
    St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
  • 78
    The Institute of Cancer Research, London, United Kingdom.
  • 79
    The M Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.
  • 80
    UPMC Univ Paris 06, GRC n°5, Institut Universitaire de Cancérologie, Paris, France.
  • 81
    University Hospitals Bristol NHS Foundation Trust National Institute for Health Research Bristol Nutrition Biomedical Research Unit, University of Bristol, Bristol, United Kingdom.
  • 82
    University of Cambridge, Cambridge, United Kingdom.
  • 83
    Van Andel Research Institute, Center for Cancer Genomics and Quantitative Biology, Grand Rapids, Michigan, United States of America.
  • 84
    Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States of America.
  • 85
    WHI Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Lipids, Blood Pressure, Mendelian Randomization Analysis, Blood Glucose, Insulin, Diabetes Mellitus, Type 2, Genetic Markers, Genome-Wide Association Study, Obesity, Kidney Neoplasms, Carcinoma, Renal Cell, Body Mass Index, Male, Female, Humans, Risk Factors
MC_UU_12013/3, MC_UU_00011/5, MC_UU_12013/1, C18281/A19169, R01 CA170298, U01 CA155309, 6858, RP-PG-0707-10101, MC_UU_12013/2
Johansson M, Carreras-Torres R, Scelo G, Purdue MP, Mariosa D, Muller DC, Timpson NJ, Haycock PC, Brown KM, Wang Z, Ye Y, Hofmann JN, Foll M, Gaborieau V, Machiela MJ, Colli LM, Li P, Garnier JG, Blanche H, Boland A, Burdette L, Prokhortchouk E, Skryabin KG, Yeager M, Radojevic-Skodric S, Ognjanovic S, Foretova L, Holcatova I, Janout V, Mates D, Mukeriya A, Rascu S, Zaridze D, Bencko V, Cybulski C, Fabianova E, Jinga V, Lissowska J, Lubinski J, Navratilova M, Rudnai P, Benhamou S, Cancel-Tassin G, Cussenot O, Weiderpass E, Ljungberg B, Tumkur Sitaram R, Häggström C, Bruinsma F, Jordan SJ, Severi G, Winship I, Hveem K, Vatten LJ, Fletcher T, Larsson SC, Wolk A, Banks RE, Selby PJ, Easton DF, Andreotti G, Beane Freeman LE, Koutros S, Männistö S, Weinstein S, Clark PE, Edwards TL, Lipworth L, Gapstur SM, Stevens VL, Carol H, Freedman ML, Pomerantz MM, Cho E, Wilson KM, Gaziano JM, Sesso HD, Freedman ND, Parker AS, Eckel-Passow JE, Huang WY, Kahnoski RJ, Lane BR, Noyes SL, Petillo D, Teh BT, Peters U, White E, Anderson GL, Johnson L, Luo J, Buring J, Lee IM, Chow WH, Moore LE, Eisen T, Henrion M, Larkin J, Barman P, Leibovich BC, Choueiri TK, Lathrop GM, Deleuze JF, Gunter M, McKay JD, Wu X, Houlston RS, Chanock SJ, Relton C, Richards JB, Martin RM, Davey Smith G, Brennan P. The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study. PLoS medicine. 2019 Jan.

Abstract

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. 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. 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.
Last Updated: 30 Apr, 2026