UDP-Glucose Ceramide Glucosyltransferase Inhibition, Immune Cell Mediation, and Endometriosis Risk: A Mendelian Randomization Study

Xue L, Zhang R, Chen J, Ge X
2025 · W7006478688
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This paper used a two-sample, two-step Mendelian randomization framework to test whether genetically predicted UDP-glucose ceramide glucosyltransferase (UGCG) inhibition is causally linked to endometriosis (EM), using GWAS data and multiple sensitivity analyses (inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO) with strict instrumental variable selection. The study found that UGCG inhibition was associated with a decreased EM risk (odds ratio 0.915, 95% CI 0.859–0.975, P=0.006). Among 731 immune cell types evaluated, 12 showed significant associations with both UGCG inhibition and EM, and 8 were identified as potential mediators, with terminally differentiated CD4+ T cells contributing the largest mediating proportion and IgD expression on IgD+ CD38dim B cells the smallest. This paper is centrally about endometriosis—specifically, it models causal effects of UGCG inhibition and immune-cell mediation on endometriosis risk.

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Abstract

Liqiu Xue,1 Rongjun Zhang,2 Jiaxing Chen,2 Xiaoxia Ge,3 Jiajing Chen4 1Department of Pathology, Jinjiang Hospital of Traditional Chinese Medicine, Jinjiang, Quanzhou, People’s Republic of China; 2Department of Pathology, Jinjiang Municipal Hospital, Fujian Campus of Shanghai Six People’s Hospital, Jinjiang, Quanzhou, People’s Republic of China; 3Department of Pathology, The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fuzhou, People’s Republic of China; 4Department of Pathology, The 910th Hospital of the Chinese People’s Liberation Army Joint Logistic Support Force, Quanzhou, People’s Republic of ChinaCorrespondence: Liqiu Xue, Jinjiang Hospital of Traditional Chinese Medicine, No. 1105 Quan’an Middle, Road, Jinjiang, Fujian, 362200, People’s Republic of China, Email [email protected]: Previous studies have reported a link between UDP-glucose ceramide glucosyltransferase (UGCG), immune regulation, and endometriosis (EM). We hypothesized that UGCG inhibitors might exert therapeutic effects on EM. Therefore, in this study, we performed a two-sample, two-step Mendelian randomization (MR) analysis modeling genetic variation of UGCG inhibitors to investigate the causal relationship between genetically determined UGCG inhibition, EM, and mediation of immune cells.Methods: Two-sample MR was conducted using genome-wide association study data on UGCG inhibition and EM. Furthermore, we adopted strict instrumental variable selection criteria to ensure the robustness of our results and primarily employed the inverse-variance weighted method, along with the weighted median, MR-Egger, and MR-PRESSO methods for sensitivity analyses. Additionally, a two-step MR analysis was performed to investigate the potential role of immune cells in mediating the relationship between UGCG inhibition and EM.Results: UGCG inhibition was associated with a decreased EM risk, with an odds ratio of 0.915, 95% confidence interval of 0.859– 0.975, and P = 0.006, demonstrating the robustness of our results and potential clinical significance of our study. Among 731 types of immune cells analyzed, 12 were significantly associated with UGCG inhibition and EM, 8 of which acted as mediators. Terminally differentiated CD4+ T cells (from the maturation stages of the T-cell panel) accounted for the highest proportion of mediating cells (26.727%), whereas immunoglobulin D (IgD) expression on IgD+ CD38dim B cells (from the B-cell panel) accounted for the lowest proportion (7.816%).Conclusion: Inhibiting UGCG activity may reduce the risk of EM, and immune cells may mediate this effect. Our findings provide novel insights for the development of potential therapeutic strategies for EM treatment. Keywords: UDP-glucose ceramide glucosyltransferase inhibition, endometriosis, immune cells, mediating effect, Mendelian randomization
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International Journal of Women's Health (May 2025) UDP-Glucose Ceramide Glucosyltransferase Inhibition, Immune Cell Mediation, and Endometriosis Risk: A Mendelian Randomization Study Abstract Liqiu Xue,1 Rongjun Zhang,2 Jiaxing Chen,2 Xiaoxia Ge,3 Jiajing Chen4 1Department of Pathology, Jinjiang Hospital of Traditional Chinese Medicine, Jinjiang, Quanzhou, People’s Republic of China; 2Department of Pathology, Jinjiang Municipal Hospital, Fujian Campus of Shanghai Six People’s Hospital, Jinjiang, Quanzhou, People’s Republic of China; 3Department of Pathology, The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Fuzhou, People’s Republic of China; 4Department of Pathology, The 910th Hospital of the Chinese People’s Liberation Army Joint Logistic Support Force, Quanzhou, People’s Republic of ChinaCorrespondence: Liqiu Xue, Jinjiang Hospital of Traditional Chinese Medicine, No. 1105 Quan’an Middle, Road, Jinjiang, Fujian, 362200, People’s Republic of China, Email [email protected]: Previous studies have reported a link between UDP-glucose ceramide glucosyltransferase (UGCG), immune regulation, and endometriosis (EM). We hypothesized that UGCG inhibitors might exert therapeutic effects on EM. Therefore, in this study, we performed a two-sample, two-step Mendelian randomization (MR) analysis modeling genetic variation of UGCG inhibitors to investigate the causal relationship between genetically determined UGCG inhibition, EM, and mediation of immune cells.Methods: Two-sample MR was conducted using genome-wide association study data on UGCG inhibition and EM. Furthermore, we adopted strict instrumental variable selection criteria to ensure the robustness of our results and primarily employed the inverse-variance weighted method, along with the weighted median, MR-Egger, and MR-PRESSO methods for sensitivity analyses. Additionally, a two-step MR analysis was performed to investigate the potential role of immune cells in mediating the relationship between UGCG inhibition and EM.Results: UGCG inhibition was associated with a decreased EM risk, with an odds ratio of 0.915, 95% confidence interval of 0.859– 0.975, and P = 0.006, demonstrating the robustness of our results and potential clinical significance of our study. Among 731 types of immune cells analyzed, 12 were significantly associated with UGCG inhibition and EM, 8 of which acted as mediators. Terminally differentiated CD4+ T cells (from the maturation stages of the T-cell panel) accounted for the highest proportion of mediating cells (26.727%), whereas immunoglobulin D (IgD) expression on IgD+ CD38dim B cells (from the B-cell panel) accounted for the lowest proportion (7.816%).Conclusion: Inhibiting UGCG activity may reduce the risk of EM, and immune cells may mediate this effect. Our findings provide novel insights for the development of potential therapeutic strategies for EM treatment. Keywords: UDP-glucose ceramide glucosyltransferase inhibition, endometriosis, immune cells, mediating effect, Mendelian randomization

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