Causal associations between Sjögren’s syndrome and subtypes of endometrial cancer

Endometrial cancer (EC) is a heterogeneous gynecologic malignancy with distinct histological subtypes and diverse etiological factors. While autoimmune diseases have been associated with cancer development, the causal relationship between Sjögren’s syndrome (SS) and EC remains unclear. In this study, we employed a Mendelian randomization (MR) approach to investigate this complex association. We conducted a two-sample MR study using genome-wide association study summary statistics from European ancestry cohorts. Genetic instruments for SS were derived from the FinnGen consortium, and outcome data for EC, including its endometrioid and non-endometrioid subtypes, were obtained from a large-scale EC meta-analysis. Multiple MR methods and sensitivity analyses were applied to assess robustness and detect pleiotropy. Genetically predicted SS was causally associated with an increased risk of overall EC (OR = 1.1480, 95% CI: 1.0511–1.2537, P = 0.0155), particularly endometrioid EC (OR = 1.1603, 95% CI: 1.0442–1.2894, P = 0.0207). No causal association was observed with non-endometrioid EC (OR = 1.0844, 95% CI: 0.8018–1.4665, P = 0.4560). Sensitivity analyses revealed no significant heterogeneity or horizontal pleiotropy, supporting the robustness of the findings. This MR study provides genetic evidence for a causal relationship between SS and increased risk of endometrioid EC, but not non-endometrioid EC. These findings suggest subtype-specific immune mechanisms underlying EC development and may inform targeted screening strategies for women with SS. Future research should explore the immuno-hormonal pathways linking autoimmunity and endometrial carcinogenesis.