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.

American Cancer Society Atlanta Georgia United States of America

AP HP Department of Urology Hopitaux Universitaires Est Parisien Tenon Paris France

Brigham and Women's Hospital Harvard Medical School Boston Massachusetts United States of America

Brown University Providence Rhode Island United States of America

Cancer Epidemiology Centre Cancer Council Victoria Melbourne Australia

Cancer Prevention Program Fred Hutchinson Cancer Research Center Seattle Washington United States of America

Cancer Science Institute of Singapore National University of Singapore Singapore Singapore

Carol Davila University of Medicine and Pharmacy Th Burghele Hospital Bucharest Romania

Centre National de Genotypage Institut de Genomique Centre de l'Energie Atomique et aux Energies Alternatives Evry France

CeRePP Paris France

Clinic of Urology Clinical Center of Serbia Belgrade Serbia

CNRS UMR8200 Institute Gustave Roussy Villejuif France

College of Human Medicine Michigan State University Grand Rapids Michigan United States of America

Dana Farber Cancer Institute Boston Massachusetts United States of America

Department of Biobank Research Umeå University Umeå Sweden

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Community Medicine University of Tromsø The Arctic University of Norway Tromsø Norway

Department of Epidemiology and Biostatistics School of Public Health Indiana University Bloomington Bloomington Indiana United States of America

Department of Epidemiology Division of Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center Houston Texas United States of America

Department of Health Sciences Research Division of Biomedical Statistics and Informatics Mayo Clinic Rochester Minnesota United States of America

Department of Health Sciences Research Mayo Clinic Jacksonville Florida United States of America

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medicine Brigham and Women's Hospital Boston Massachusetts United States of America

Department of Medicine Division of Epidemiology Vanderbilt Ingram Cancer Center Vanderbilt Genetics Institute Nashville Tennessee United States of America

Department of Medicine Royal Melbourne Hospital University of Melbourne Melbourne Australia

Department of Oncology University of Cambridge Cambridge United Kingdom

Department of Preventive Medicine Faculty of Medicine Palacky University Olomouc Czech Republic

Department of Public Health and General Practice Faculty of Medicine Norwegian University of Science and Technology Trondheim Norway

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Department of Research Cancer Registry of Norway Institute of Population Based Cancer Research Oslo Norway

Department of Surgical and Perioperative Sciences Urology and Andrology Umeå University Umeå Sweden

Department of Surgical Sciences Uppsala University Uppsala Sweden

Department of Urology Mayo Clinic Rochester Minnesota United States of America

Departments of Medicine Human Genetics Epidemiology and Biostatistics Jewish General Hospital McGill University Montreal Quebec Canada

Dept of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York United States of America

Diagnostics Program at Ferris State University Grand Rapids Michigan United States of America

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Department Health and Human Services Bethesda Maryland United States of America

Division of Urology Spectrum Health Grand Rapids Michigan United States of America

Federal Research Centre Fundamentals of Biotechnology of the Russian Academy of Sciences Moscow Russian Federation

Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain Paris France

Fred Hutchinson Cancer Research Center Seattle Washington United States of America

Genetic Epidemiology Group Folkhälsan Research Center Helsinki Finland

Harvard T H Chan School of Public Health Boston Massachusetts United States of America

Health across generations team CESP Inserm Facultés de Médicine Université Paris Sud UVSQ Université Paris Saclay Gustave Roussy Villejuif France

Human Genetics Foundation Torino Italy

Imperial College London United Kingdom

INSERM U946 Paris France

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Molecular and Cell Biology A*STAR Singapore Singapore

Institute of Pathology Medical School of Belgrade Belgrade Serbia

Institute of Public Health and Preventive Medicine 2nd Faculty of Medicine Charles University Prague Czech Republic

International Agency for Research on Cancer Lyon France

International Hereditary Cancer Center Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

International Organization for Cancer Prevention and Research Belgrade Serbia

K G Jebsen Center for Genetic Epidemiology Department of Public Health Norwegian University of Science and Technology Trondheim Norway

Kurchatov Scientific Center Moscow Russian Federation

Laboratory of Cancer Epigenome Division of Medical Sciences National Cancer Centre Singapore Singapore Singapore

Leeds Institute of Cancer and Pathology University of Leeds St James's University Hospital Leeds United Kingdom

London School of Hygiene and Tropical Medicine University of London London United Kingdom

Max Planck Institute for Demographic Research Rostock Germany

Mayo Clinic Graduate School of Biomedical Sciences Rochester Minnesota United States of America

McGill University and Genome Quebec Innovation Centre Montreal Quebec Canada

MRC Integrative Epidemiology Unit University of Bristol Bristol United Kingdom

National Institute for Health and Welfare Helsinki Finland

National Institute for Health Research Diagnostic Evidence Cooperative Division of Surgery Imperial College London St Mary's Hospital London United Kingdom

National Institute of Public Health Bucharest Romania

National Public Health Center National Directorate of Environmental Health Budapest Hungary

Program in Cancer and Stem Cell Biology Duke National University of Singapore Medical School Singapore Singapore

QIMR Berghofer Medical Research Institute Herston Queensland Australia

Regional Authority of Public Health in Banska Bystrica Banska Bystrica Slovakia

Royal Marsden NHS Foundation Trust London United Kingdom

Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

School of Public Health The University of Queensland Brisbane Australia

School of Social and Community Medicine University of Bristol Bristol United Kingdom

Spectrum Health Grand Rapids Michigan United States of America

St Jude Children's Research Hospital Memphis Tennessee United States of America

The Institute of Cancer Research London United Kingdom

The M Sklodowska Curie Cancer Center and Institute of Oncology Warsaw Poland

University Hospitals Bristol NHS Foundation Trust National Institute for Health Research Bristol Nutrition Biomedical Research Unit University of Bristol Bristol United Kingdom

University of Cambridge Cambridge United Kingdom

UPMC Univ Paris 06 GRC n°5 Institut Universitaire de Cancérologie Paris France

Van Andel Research Institute Center for Cancer Genomics and Quantitative Biology Grand Rapids Michigan United States of America

Vanderbilt Ingram Cancer Center Nashville Tennessee United States of America

WHI Clinical Coordinating Center Fred Hutchinson Cancer Research Center Seattle Washington United States of America

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