Alcohol Consumption and Endometrial Cancer: A Mendelian Randomization Study

Background: Endometrial cancer (EC) is a common gynecological tumor in females with an increasing incidence over the past few decades. Alcohol consumption has been linked to the occurrence of various cancers; however, epidemiological studies have shown inconsistent associations between alcohol consumption and EC risk. This study aimed to investigate whether there is a causal relationship between alcohol consumption and EC. Methods: Mendelian randomization (MR) analysis was conducted using publicly available summary-level data from genome-wide association studies (GWAS). Fifty-seven single nucleotide polymorphisms (SNPs) were extracted as instrumental variables for alcohol exposure from the Social Science Genetic Association Consortium (SSGAC) GWAS summary data involving 941,287 participants of European ancestry. SNPs for EC were obtained from the Endometrial Cancer Association Consortium, the Endometrial Cancer Epidemiology Consortium, and the UK Biobank, involving 121,885 European participants. The inverse variance weighted (IVW) method was used as the primary method to estimate the causal effect, and the MR-Egger regression and weighted median method were used as supplementary methods. Sensitivity analyses were conducted using the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test, MR-Egger intercept test, and leave-one-out analysis to evaluate the impact of pleiotropy on causal estimates. Results: An increase of 1 standard deviation (SD) of genetically predicted log-transformed alcoholic drinks per day was associated with a 43% reduction in EC risk (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.41–0.79; P༜0.001). Subgroup analysis of EC revealed that alcohol consumption was a protective factor for endometrioid endometrial cancer (EEC) (OR, 0.56; 95% CI, 0.38–0.83; P = 0.004) but not for non-endometrioid endometrial cancer (NEC) (OR, 1.36; 95% CI, 0.40–4.66; P = 0.626). The MR-Egger regression and weighted median method yielded consistent causal effects with the IVW method. The consistent results of sensitivity analyses indicated the reliability of our causal estimates. Additionally, alcohol consumption was associated with decreased human chorionic gonadotropin (HCG) and insulin-like growth factor 1 (IGF1) levels. Conclusion: This study suggests that alcohol consumption is a protective factor for EC, particularly for EEC, and this protective effect may be mediated through the reduction of HCG and IGF1.