A deep transcriptome meta-analysis reveals sex-based molecular differences in Multiple Sclerosis

Background: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory, and degenerative disease of the central nervous system that affects both women and men but the risk of developing MS is higher in women (2-3:1 ratio compared to men). Current knowledge does not allow a precise definition of the sex-related factors intervening in MS. Here, we explore the role of sex in this neurodenegerative disease to identify molecular mechanisms underlying sex-based diferences that can guide novel therapeutics approaches aimed for men and women. Methods: We performed a rigorous and systematic review of MS whole transcriptome studies that included sex patient information in Gene Expression Omnibus and ArrayExpress databases, following PRISMA statment guidelines. A differential gene expression (DGE) was performed for each selected study. Then, three meta-analyses based on genes and different contrasts were addressed to evaluate common features and sex bias in all scenarios: one meta-analysis in nervous tissue studies (4), another in blood studies (5), and a third that integrated the studies from both tissues, blood and nervous system (9). Finally, a gene set analysis (GSA) was performed on the meta-analyzed differential transcriptomic profile between women and men, to study their involvement in biological pathways and phenotypes (physiological and pathological states) sex related. Results: After screening 122 publications, the systematic review provided a selection of nine studies (5 in blood and 4 in nervous tissue) with a total of 653 samples (269 MS women, 152 control women, 116 MS men, 116 control men). The blood sex-differences gene meta-analysis identified 1 gene overexpressed in women (KIR2DL3) while gene meta-analysis in the nervous tissue resulted in 5 genes differentially expressed (4 overexpressed in women: C7orf73, CECR7, TRAF3IP2-AS1, ZNF117; and 1 overexpressed in men: HIST1H2AE). In the global meta-analysis (blood and nervous tissue), 1 gene involved in sex differences were detected (more expressed in women: LOC102723701). 9 MS biomarkers were also identified in both sexes (4 overexpressed genes in MS patients: HIST1H2BC, SMEK2, STBD1, TMEM140) and 5 down-regulated in MS patients: C16orf59, C20orf177, C9orf23, FAM65B, PKI55). Additionally, the GSA related to gene meta-analysis revealed a set of functions differentially enriched in men and women, in the different analysed tissues. Conclusion: These findings provide valuable opportunities for better understanding of MS related sex differences and develop effective and sex-specific interventions down further studies.