Nabila Kazmi1,2, Philip Haycock1,2, Konstantinos Tsilidis3,4, Brigid M Lynch5,6,7, Therese Truong8, Richard M Martin1,2,9, Sarah J Lewis1,2. 1. MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK. 2. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 3. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. 4. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. 5. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia. 6. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia. 7. Physical-Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia. 8. Université Paris-Saclay, Université Paris-Sud, CESP (Center for Research in Epidemiology and Population Health), INSERM, Team Cancer and Environment, Villejuif, France. 9. National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals NHS Trust and University of Bristol, Bristol, UK.
Abstract
BACKGROUND: Prostate cancer is the second most common male cancer worldwide, but there is substantial geographical variation, suggesting a potential role for modifiable risk factors in prostate carcinogenesis. METHODS: We identified previously reported prostate cancer risk factors from the World Cancer Research Fund (WCRF)'s systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79 148 cases and 61 106 controls) or aggressive (15 167 cases and 58 308 controls) prostate cancer using Mendelian randomization (MR) based on genome-wide association-study summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7844 prostate-cancer cases and 204 001 controls). RESULTS: WCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms. For overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical activity, OR = 0.49 (0.33-0.72; P = 0.0003); serum iron, OR = 0.92 (0.86-0.98; P = 0.007); body mass index (BMI), OR = 0.90 (0.84-0.97; P = 0.003); and monounsaturated fat, OR = 1.11 (1.02-1.20; P = 0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive-prostate-cancer risk: OR = 1.07 (1.01-1.15; P = 0.03). CONCLUSIONS: The results for physical activity, serum iron, BMI, monounsaturated fat and height are compatible with causality for prostate cancer. The results suggest that interventions aimed at increasing physical activity may reduce prostate-cancer risk, although interventions to change other risk factors may have negative consequences on other diseases.
BACKGROUND:Prostate cancer is the second most common male cancer worldwide, but there is substantial geographical variation, suggesting a potential role for modifiable risk factors in prostate carcinogenesis. METHODS: We identified previously reported prostate cancer risk factors from the World Cancer Research Fund (WCRF)'s systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79 148 cases and 61 106 controls) or aggressive (15 167 cases and 58 308 controls) prostate cancer using Mendelian randomization (MR) based on genome-wide association-study summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7844 prostate-cancer cases and 204 001 controls). RESULTS: WCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms. For overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical activity, OR = 0.49 (0.33-0.72; P = 0.0003); serum iron, OR = 0.92 (0.86-0.98; P = 0.007); body mass index (BMI), OR = 0.90 (0.84-0.97; P = 0.003); and monounsaturated fat, OR = 1.11 (1.02-1.20; P = 0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive-prostate-cancer risk: OR = 1.07 (1.01-1.15; P = 0.03). CONCLUSIONS: The results for physical activity, serum iron, BMI, monounsaturated fat and height are compatible with causality for prostate cancer. The results suggest that interventions aimed at increasing physical activity may reduce prostate-cancer risk, although interventions to change other risk factors may have negative consequences on other diseases.
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