Elevated Neutrophil Count as a Causal Risk Factor for Endometriosis: A Mendelian Randomization Study

Meihua Li,1 Xiaohua Zhou,2 Yu Chen11Department of Gynecology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, Hunan, 415000, People’s Republic of China; 2Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Yu Chen, Department of Gynecology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), No. 818 Renmin Road, Wuling District, Changde, Hunan, 415000, People’s Republic of China, Tel +86-15807363133, Email [email protected]: Endometriosis is a chronic inflammatory gynecological disorder where immune dysregulation plays a central role in its pathogenesis. While previous observational studies have reported associations between circulating blood cell counts and endometriosis risk, it remains unclear whether these hematological alterations are a causal factor or merely a secondary consequence of the disease itself. This study used a bidirectional two-sample Mendelian randomization (MR) approach to investigate causal relationships between six circulating blood cell counts and endometriosis risk.Methods: We conducted bidirectional two-sample MR analyses using GWAS summary statistics from a meta-analysis of up to 563,946 individuals (blood cell traits) and the FinnGen R12 release (endometriosis: 18,349 cases, 208,924 controls). Genetic instruments included basophil, eosinophil, lymphocyte, monocyte, neutrophil, and total white blood cell counts. The inverse-variance weighted method served as the primary analysis, supported by MR-Egger, weighted median, Cochran’s Q test, and leave-one-out analyses.Results: Forward MR analysis revealed that genetically predicted higher neutrophil count was causally associated with increased endometriosis risk (Odds Ratio [OR] = 1.113, 95% Confidence Interval [CI]: 1.038– 1.194, P = 0.003). A similar significant causal effect was also found for total white blood cell count (OR = 1.096, 95% CI: 1.028– 1.169, P = 0.005). Both associations remained significant after false discovery rate correction. No significant causal effects were observed for basophil, eosinophil, monocyte, or lymphocyte counts. The reverse MR analysis found no evidence of a causal effect of endometriosis liability on any blood cell trait.Conclusion: This study provides robust genetic evidence that an elevated neutrophil count is a causal risk factor for endometriosis, establishing systemic innate inflammation as a primary contributor to disease etiology rather than merely a secondary consequence. These findings highlight neutrophil-mediated inflammatory pathways as promising targets for novel therapeutic and preventive strategies in endometriosis.Keywords: endometriosis, inflammation, blood cells, neutrophil count, white blood cell count, Mendelian randomization, causal inference, genetic epidemiology