Complement and coagulation cascade crosstalk in endometriosis and the potential of JAK inhibitors - a network meta-analysis

BackgroundLack of knowledge on the processes driving endometriosis hinders early detection and therapy development. Our purpose was to identify key molecular events involved in lesion formation across diverse populations and to detect transcriptomic changes in eutopic endometrium that accompany endometriosis. MethodsWe searched Gene Expression Omnibus and ArrayExpress and performed differential gene expression analysis and a network meta-analysis on nine qualifying datasets. Those contained transcriptomic data on: 114 ectopic endometrium samples (EL), 138 eutopic endometrium samples from women with endometriosis (EEM) and 79 eutopic endometrium samples from women without endometriosis (EH). Gene ontology and enrichment analysis was performed in DAVID, Metascape and Cytoscape and drug repurposing was done in CMap. ResultsEEM compared to EH upregulated CCL21 and downregulated BIRC3, CEL and LEFTY1 genes (|log2FC|>0.5, p<0.05). EL showed increased expression of complement and serpin genes (EL vs EEM: C7, logFC = 3.38, p <0.0001; C3, logFC = 2.40, p<0.0001; SERPINE1, logFC = 1.02; p<0.05; SERPINE2, logFC = 1.54, p<0.001) and mast cells markers (EL vs EEM: CPA3, logFC = 1.54, p<0.0001, KIT, logFC=0.74, p<0.001). Functional enrichment analysis highlighted complement and coagulation, inflammation, angiogenesis and ECM as drivers of endometriosis. Pharmacogenomic analysis indicated JAK, CDK and topoisomerase inhibitors as therapy targets. ConclusionOur results suggest an interplay between complement and coagulation, mast cells, ECM and JAK/STAT3 pathway in endometriosis. We underscore the significance of complement C3 and propose JAK inhibitors as therapy candidates. Detected expression differences between EEM and EH are important for the development of diagnosis via endometrial biopsy. WHAT IS ALREADY KNOWN ON THIS TOPICPathways and genes involved in endometriosis lesions formation are not well characterised. Studies encompassing diverse patients populations are missing. WHAT THIS STUDY ADDSThis study reveals the transcriptomic profile of endometriosis, obtained via integration of nine different datasets spanning various ethnicities and demographics. It demonstrates the importance of complement and coagulation cascades, mast cells and JAK/STAT3 pathway in lesion development. Our meta-analysis identifies transcriptomic differences in eutopic endometrium of women with and without endometriosis which include changes in CCL21, BIRC3, CEL and LEFTY1 expression. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYOur comprehensive analysis of endometriosis transcriptomic profile highlights genes and pathways that should be explored further as disease biomarkers. JAK inhibitors currently used in clinic in other autoimmune diseases show treatment potential. Gene expression differences between eutopic endometrium of women with and without endometriosis should be further explored as biomarkers in endometrial biopsy.