Jingjing Zhu1, Xia Jiang2, Zheng Niu3. 1. The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China. 2. Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden. 3. Department of Gynecology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, China. Electronic address: nhelenn@163.com.
Abstract
BACKGROUND: Alcohol consumption has been found to increase the risk of breast cancer in observation studies, yet it remains unknown if alcohol is related to other hormone-dependent cancers such as ovarian cancer. No Mendelian randomization (MR) studies have been performed to assess a potential causal relationship between alcohol use and risk of breast and ovarian cancer. METHODS: We aim to determine if alcohol consumption is causally associated with the risk of female hormone-dependent cancers, by using summary level genetic data from the hitherto largest genome-wide association studies (GWAS) conducted on alcohol consumption (N=~1.5 million individuals), breast (Ncase=122,977) and ovarian cancer (Ncase=25,509). We examined three different alcohol intake exposures, drinks per week (drinks/week), alcohol use disorder (AUD) and age-adjusted alcohol use disorder identification test (AUDIT-C), to reflect the general and harmful drinking behavior. We constructed updated and stronger instruments using ninety-nine drinks/week-related SNPs, nine AUD-related SNPs and thirteen AUDIT-C-related SNPs and estimated the causal relationship applying several two-sample MR methods. RESULTS: We did not find any evidence to support for a causal association between alcohol consumption and risk of breast cancer [ORdrinks/week=1.01 (0.85-1.21), P=0.89; ORAUD=1.04 (95%CI: 0.89-1.21), P=0.62; ORAUDIT-C=1.07 (0.90-1.28), P=0.44]; neither with its subtypes including ER-positive and ER-negative breast cancer, using any of the three alcohol-related exposures. For ovarian cancer, however, we identified a reduced risk with alcohol consumption, where a borderline significance was found for AUDIT-C but not for drinks/week or AUC [ORdrinks/week=0.83 (0.63-1.10), P=0.19; ORAUD=0.92 (0.83-1.01), P=0.08; ORAUDIT-C=0.83 (0.71-0.97), P=0.02]. The effect attenuated to null excluding SNPs associated with potential confounders [ORdrinks/week=0.81(0.53-1.21), P=0.31; ORAUD=0.96(0.78-1.18), P=0.68; ORAUDIT-C=0.89(0.68-1.16), P=0.38]. CONCLUSION: We do not find any compelling evidence in support for a causal relationship between genetically predicted alcohol consumption and risk of breast or ovarian cancer, consistent across three different alcohol-related exposures. Future MR studies validating our findings are needed, when large-scale alcohol consumption GWAS results become available.
BACKGROUND:Alcohol consumption has been found to increase the risk of breast cancer in observation studies, yet it remains unknown if alcohol is related to other hormone-dependent cancers such as ovarian cancer. No Mendelian randomization (MR) studies have been performed to assess a potential causal relationship between alcohol use and risk of breast and ovarian cancer. METHODS: We aim to determine if alcohol consumption is causally associated with the risk of female hormone-dependent cancers, by using summary level genetic data from the hitherto largest genome-wide association studies (GWAS) conducted on alcohol consumption (N=~1.5 million individuals), breast (Ncase=122,977) and ovarian cancer (Ncase=25,509). We examined three different alcohol intake exposures, drinks per week (drinks/week), alcohol use disorder (AUD) and age-adjusted alcohol use disorder identification test (AUDIT-C), to reflect the general and harmful drinking behavior. We constructed updated and stronger instruments using ninety-nine drinks/week-related SNPs, nine AUD-related SNPs and thirteen AUDIT-C-related SNPs and estimated the causal relationship applying several two-sample MR methods. RESULTS: We did not find any evidence to support for a causal association between alcohol consumption and risk of breast cancer [ORdrinks/week=1.01 (0.85-1.21), P=0.89; ORAUD=1.04 (95%CI: 0.89-1.21), P=0.62; ORAUDIT-C=1.07 (0.90-1.28), P=0.44]; neither with its subtypes including ER-positive and ER-negative breast cancer, using any of the three alcohol-related exposures. For ovarian cancer, however, we identified a reduced risk with alcohol consumption, where a borderline significance was found for AUDIT-C but not for drinks/week or AUC [ORdrinks/week=0.83 (0.63-1.10), P=0.19; ORAUD=0.92 (0.83-1.01), P=0.08; ORAUDIT-C=0.83 (0.71-0.97), P=0.02]. The effect attenuated to null excluding SNPs associated with potential confounders [ORdrinks/week=0.81(0.53-1.21), P=0.31; ORAUD=0.96(0.78-1.18), P=0.68; ORAUDIT-C=0.89(0.68-1.16), P=0.38]. CONCLUSION: We do not find any compelling evidence in support for a causal relationship between genetically predicted alcohol consumption and risk of breast or ovarian cancer, consistent across three different alcohol-related exposures. Future MR studies validating our findings are needed, when large-scale alcohol consumption GWAS results become available.
Authors: Lauren E McCullough; Maret L Maliniak; Avnika B Amin; Julia M Baker; Davit Baliashvili; Julie Barberio; Chloe M Barrera; Carolyn A Brown; Lindsay J Collin; Alexa A Freedman; David C Gibbs; Maryam B Haddad; Eric W Hall; Sarah Hamid; Kristin R V Harrington; Aaron M Holleman; John A Kaufman; Mohammed A Khan; Katie Labgold; Veronica C Lee; Amyn A Malik; Laura M Mann; Kristin J Marks; Kristin N Nelson; Zerleen S Quader; Katherine Ross-Driscoll; Supriya Sarkar; Monica P Shah; Iris Y Shao; Jonathan P Smith; Kaitlyn K Stanhope; Marisol Valenzuela-Lara; Miriam E Van Dyke; Kartavya J Vyas; Timothy L Lash Journal: Sci Adv Date: 2022-06-08 Impact factor: 14.957