Zhu Jingjing, Jiang Xia, Niu Zheng
The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
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.
Cancer Genet. 2020 Jul;245:35-41. doi: 10.1016/j.cancergen.2020.06.001. Epub 2020 Jun 12.
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.
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 (N=122,977) and ovarian cancer (N=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.
We did not find any evidence to support for a causal association between alcohol consumption and risk of breast cancer [OR=1.01 (0.85-1.21), P=0.89; OR=1.04 (95%CI: 0.89-1.21), P=0.62; OR=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 [OR=0.83 (0.63-1.10), P=0.19; OR=0.92 (0.83-1.01), P=0.08; OR=0.83 (0.71-0.97), P=0.02]. The effect attenuated to null excluding SNPs associated with potential confounders [OR=0.81(0.53-1.21), P=0.31; OR=0.96(0.78-1.18), P=0.68; OR=0.89(0.68-1.16), P=0.38].
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.
在观察性研究中发现饮酒会增加患乳腺癌的风险，但尚不清楚酒精是否与其他激素依赖性癌症（如卵巢癌）有关。尚未进行孟德尔随机化（MR）研究来评估饮酒与乳腺癌和卵巢癌风险之间的潜在因果关系。
我们旨在通过使用来自迄今为止最大规模的关于饮酒（N=约150万人）、乳腺癌（N=122977）和卵巢癌（N=25509）的全基因组关联研究（GWAS）的汇总水平遗传数据，来确定饮酒是否与女性激素依赖性癌症的风险存在因果关系。我们研究了三种不同的酒精摄入量暴露情况，即每周饮酒量（杯/周）、酒精使用障碍（AUD）和年龄调整后的酒精使用障碍识别测试（AUDIT-C），以反映一般和有害的饮酒行为。我们使用99个与每周饮酒量相关的单核苷酸多态性（SNP）、9个与AUD相关的SNP和13个与AUDIT-C相关的SNP构建了更新且更强有力的工具变量，并应用几种两样本MR方法估计因果关系。
我们没有发现任何证据支持饮酒与乳腺癌风险之间存在因果关联[比值比（OR）=1.01（0.85 - 1.21），P = 0.89；OR = 1.04（95%置信区间：0.89 - 1.21），P = 0.62；OR = 1.07（0.90 - 1.28），P =
