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 (N_case=122,977) and ovarian cancer (N_case=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 [OR_drinks/week=1.01 (0.85–1.21), P=0.89; OR_AUD=1.04 (95%CI: 0.89–1.21), P=0.62; OR_AUDIT-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 [OR_drinks/week=0.83 (0.63–1.10), P=0.19; OR_AUD=0.92 (0.83–1.01), P=0.08; OR_AUDIT-C=0.83 (0.71–0.97), P=0.02]. The effect attenuated to null excluding SNPs associated with potential confounders [OR_drinks/week=0.81(0.53–1.21), P=0.31; OR_AUD=0.96(0.78–1.18), P=0.68; OR_AUDIT-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.

中文翻译：

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饮酒与乳腺癌和卵巢癌的风险：孟德尔随机研究。

背景

在观察研究中发现饮酒会增加患乳腺癌的风险，但酒精是否与其他激素依赖性癌症（例如卵巢癌）有关仍是未知的。尚无孟德尔随机（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。

方法

我们的目的是通过使用迄今最大的关于饮酒的全基因组关联研究（GWAS）（N =〜150万个人），利用汇总水平的遗传数据来确定饮酒是否与女性激素依赖型癌症的风险有因果关系。，乳腺癌（N_例= 122,977）和卵巢癌（N_例= 25,509）。我们检查了三种不同的酒精摄入量，每周（饮料/周）饮酒，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。我们构建了使用99种与饮料/周相关的SNP，9种与AUD相关的SNP和13种与AUDIT-C相关的SNP的更新且更强大的工具，并使用几种两样本MR方法估算了因果关系。

结果

我们没有发现任何证据支持饮酒与乳腺癌风险之间的因果关系[OR_饮料/周= 1.01（0.85–1.21），P = 0.89；或_AUD = 1.04（95％CI：0.89–1.21），P = 0.62；或_AUDIT-C = 1.07（0.90-1.28），P = 0.44]；均未使用三种与酒精有关的暴露中的任何一种，包括亚型（包括ER阳性和ER阴性乳腺癌）。但是，对于卵巢癌，我们发现饮酒的风险降低了，发现对AUDIT-C而言具有临界意义，但对于饮料/周或AUC则没有临界意义[OR_饮料/周= 0.83（0.63-1.10），P = 0.19；或_AUD = 0.92（0.83-1.01），P = 0.08；要么_AUDIT-C = 0.83（0.71-0.97），P = 0.02]。除了与潜在混杂因素相关的SNP之外，效应减弱为零[OR_饮料/周= 0.81（0.53-1.21），P = 0.31；或_AUD = 0.96（0.78-1.18），P = 0.68；或_AUDIT-C = 0.89（0.68-1.16），P = 0.38]。

结论

我们没有任何令人信服的证据支持遗传预测的饮酒与乳腺癌或卵巢癌风险之间的因果关系，这在三种与酒精有关的暴露中均保持一致。当大规模饮酒GWAS结果可用时，需要进一步的MR研究来验证我们的发现。