Journal
PLOS MEDICINE
Volume 16, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pmed.1002724
Keywords
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Categories
Funding
- World Cancer Research Fund International [2014/1193]
- Cancer Research UK [C18281/A19169]
- US National Institutes of Health (NIH), National Cancer Institute [U01CA155309]
- National Cancer Institute, US NIH
- NIH [R01 CA170298]
- Center for Translational and Public Health Genomics
- Duncan Family Institute for Cancer Prevention and Risk Assessment
- University of Texas MD Anderson Cancer Center
- National Institute for Health Research (NIHR) Bristol Nutritional Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol
- MRC Integrative Epidemiology Unit at the University of Bristol [MC_UU_12013/1, MC_UU_12013/2, MC_UU_12013/3]
- Canadian Institutes of Health Research
- Fonds du Recherche Quebec-Sante
- RM/ICR NIHR Biomedical Research Centre for Cancer
- MRC [MC_UU_12013/2, MC_UU_12013/3, MC_UU_00011/5, MC_UU_12013/1] Funding Source: UKRI
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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.
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