Department of Big Data in Health Science School of Public Health, and Centre of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, China.
Eur J Epidemiol. 2022 Jul;37(7):701-712. doi: 10.1007/s10654-022-00886-1. Epub 2022 Jun 16.
Alcohol intake is thought to be a risk factor for breast cancer, but the causal relationship and carcinogenic mechanisms are not clear. We performed an up-to-date meta-analysis of prospective studies to assess observational association, and then conducted MR analysis to make causal inference based on the genetic predisposition to alcohol consumption ("drinks per week") and pathological drinking behaviours ("alcohol use disorder" and "problematic alcohol use"), as well as genetically predicted DNA methylation at by alcohol-related CpG sites in blood. We found an observational dose-response association between alcohol intake and breast cancer incidence with an additional risk of 4% for per 10 g/day increase in alcohol consumption. Genetic predisposition to alcohol consumption ("drinks per week") was not causally associated with breast cancer incidence at the OR of 1.01 (95% CI 0.84, 1.23), but problematic alcohol use (PAU) was linked to a higher breast cancer risk at the OR of 1.76 (95% CI 1.04, 2.99) when conditioning on alcohol consumption. Epigenetic MR analysis identified four CpG sites, cg03260624 near CDC7 gene, cg10816169 near ZNF318 gene, cg03345232 near RIN3 gene, and cg26312998 near RP11-867G23.13 gene, where genetically predicted epigenetic modifications were associated with an increased breast cancer incidence risk. Our findings re-affirmed that alcohol consumption is of high risk for breast cancer incidence even at a very low dose, and the pathogenic effect of alcohol on breast cancer could be due to pathological drinking behaviour and epigenetic modification at several CpG sites, which could be potential intervention targets for breast cancer prevention.
饮酒被认为是乳腺癌的一个风险因素，但因果关系和致癌机制尚不清楚。我们对前瞻性研究进行了最新的荟萃分析，以评估观察性关联，然后进行 MR 分析，根据饮酒的遗传易感性（“每周饮酒量”）和病理性饮酒行为（“酒精使用障碍”和“问题性饮酒”），以及血液中与酒精相关的 CpG 位点的遗传预测 DNA 甲基化，得出因果推断。我们发现饮酒量与乳腺癌发病率之间存在观察到的剂量反应关联，每增加 10 克/天的饮酒量，乳腺癌的额外风险增加 4%。饮酒的遗传易感性（“每周饮酒量”）与乳腺癌发病率无因果关联，比值比为 1.01（95%置信区间 0.84，1.23），但在考虑到饮酒量的情况下，问题性饮酒（PAU）与乳腺癌风险增加相关，比值比为 1.76（95%置信区间 1.04，2.99）。基于遗传预测的表观遗传 MR 分析确定了四个 CpG 位点，CDC7 基因附近的 cg03260624、ZNF318 基因附近的 cg10816169、RIN3 基因附近的 cg03345232 和 RP11-867G23.13 基因附近的 cg26312998，其中遗传预测的表观遗传修饰与乳腺癌发病率升高相关。我们的研究结果再次证实，即使饮酒量很低，也会大大增加乳腺癌发病率的风险，酒精对乳腺癌的致病作用可能归因于病理性饮酒行为和几个 CpG 位点的表观遗传修饰，这些修饰可能是乳腺癌预防的潜在干预靶点。
