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Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study.

Published version
Peer-reviewed

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Authors

Brunner, Clair 
Davies, Neil M 
Martin, Richard M 
Eeles, Rosalind 

Abstract

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed  = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed  = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.

Description

Keywords

Mendelian randomisation, alcohol, alcohol metabolising genes, prostate cancer, Aged, Aged, 80 and over, Alcohol Drinking, Aldehyde Dehydrogenase, Aldehyde Dehydrogenase 1 Family, Aldehyde Dehydrogenase, Mitochondrial, Case-Control Studies, Disease Progression, Humans, Incidence, Linkage Disequilibrium, Male, Middle Aged, Neoplasm Grading, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Regression Analysis, Retinal Dehydrogenase, Survival Analysis

Journal Title

Int J Cancer

Conference Name

Journal ISSN

0020-7136
1097-0215

Volume Title

140

Publisher

Wiley
Sponsorship
Medical Research Council (MR/N003284/1)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
National Cancer Institute (R01CA128978)
Cancer Research UK (12014)
Cancer Research UK (10118)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
National Institute for Health Research (NIHR) (via University of Oxford) (HTA no. 96/20/99)
TCC (None)
Medical Research Council (G0401527/1)
This work was supported by a Cancer Research UK (C18281/A19169) programme grant to RMM and Caroline Relton (Integrative Cancer Epidemiology Programme). LZ was funded by a UK MRC Special Training Fellowship (G0501864/76656) and a UK MRC Population Health Scientist fellowship [grant number G0902144]. LZ and NMD work in a unit that receives funding from the UK MRC [G0600705] and the University of Bristol (MC_UU _12013/1,9). The CRUK study and the PRACTICAL consortium were supported by the Canadian Institutes of Health Research; the European Commission's Seventh Framework Programme grant agreement number 223175 (HEALTH-F2-2009-223175); Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A1069 2, C16913/A6135; and the National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009- 223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15 007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The ProtecT study is funded by the U.K. Health Technology Assessment (HTA) Programme of the NIH Research (HTA 96/20/99; ISRCTN 20141297). The authors thank the provision of the additional epidemiological data by the NHS R&D Directorate supported Prodigal study and the ProMPT (Prostate Mechanisms of Progression and Treatment) collaboration which is supported by the National Cancer Research Institute (NCRI) formed by the Department of Health, the Medical Research Council and Cancer Research UK (G0500966/75466). RAE and ZKJ are supported by Cancer Research UK Grant C5047/A7357 and the NIHR Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust. RMM was supported by the National Institute for Health Research Bristol Nutrition Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. FCH, DEN and JLD are NIHR Senior Investigators.