Genetic Causal Relationship Between Systemic Lupus Erythematosus and Malignant Tumors of the Female Reproductive System: A GWAS Analysis in European Populations

<b>Background:</b> Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women of reproductive age. Existing studies have demonstrated complex associations between SLE and various diseases, but its genetic relationship with malignant tumors of the female reproductive system has not been fully elucidated. This study is aimed at exploring the potential genetic associations and shared molecular basis between SLE and female reproductive system malignancies using genome-wide association studies (GWASs) and cross-trait analysis. <b>Methods:</b> We selected genetic variants significantly associated with SLE (<i>p</i> < 5 × 10^-8) from large-scale GWAS databases as genetic instruments and applied various statistical methods to analyze the associations between SLE and cervical cancer, endometrial cancer, ovarian cancer, vulvar cancer, vaginal cancer, and uterine cancer. The primary analysis was conducted using inverse variance weighting (IVW), supplemented by Egger regression, weighted median, and weighted mode methods. To control for potential confounders, we performed multivariable analysis while including BMI, estradiol, and CRP as covariates. Additionally, cross-trait analysis using the association analysis based on subset (ASSET) method was employed to identify shared genetic variants and their effect directions between SLE and uterine cancer. <b>Results:</b> Genetic association analysis showed a significant negative association between SLE and endometrial cancer (OR = 0.972, 95% CI [0.946-0.998], <i>p</i> = 0.038), suggesting that SLE may be associated with a reduced risk of endometrial cancer. For uterine cancer, the weighted median method also indicated a marginally significant negative association (OR = 0.955, 95% CI [0.912-1.000], <i>p</i> = 0.049). Multivariable analysis further confirmed that the protective association between SLE and endometrial cancer remained significant after controlling for BMI, estradiol, and CRP (OR = 0.96, 95% CI [0.93-0.99], <i>p</i> = 0.014). However, no significant association was observed between SLE and cervical cancer, ovarian cancer, vulvar cancer, or vaginal cancer. Cross-trait analysis identified 193 shared genetic variants between SLE and endometrial cancer and 71 shared variants between SLE and uterine cancer, with rs2442719 and rs3131004 showing consistent effect directions in both comparisons. <b>Conclusion:</b> This study provides genetic epidemiological evidence suggesting that SLE may have a protective effect against endometrial and uterine cancers and identifies potential shared genetic bases. These findings offer new insights into the relationship between SLE and gynecological tumors and may provide references for the prevention and treatment of related diseases.