A Deep Transcriptome Meta-Analysis Reveals Sex-based Molecular Differences in Multiple Sclerosis

Abstract Background Multiple sclerosis (MS), a chronic auto-immune, inflammatory, and degenerative disease of the central nervous system, affects both males and females; however, females suffer from a higher risk of developing MS (2-3:1 ratio compared to males). Current knowledge does not allow a precise definition of the sex-based factors influencing MS. Here, we explore the role of sex in MS to identify potential molecular mechanisms underlying sex-based differences that may guide novel therapeutic approaches tailored for males or females. Methods We performed a rigorous and systematic review of whole transcriptome studies of MS that included patient information regarding sex in Gene Expression Omnibus and ArrayExpress databases following PRISMA statement guidelines. We analyzed differential gene expression for each selected study and addressed 3 meta-analyses based on genes to evaluate common features and sex bias: the first meta-analysis of 4 nervous tissue studies, a second in 5 blood studies, and a third integrating 9 studies from both tissues. Finally, we performed a gene set analysis on the meta-analyzed differential transcriptomic profiles of the nervous system to study sex-based differences in biological pathways and phenotypes (physiological and pathological states). Results After screening 122 publications, the systematic review provided a selection of 9 studies (5 in blood and 4 in nervous tissue) with a total of 474 samples (189 MS females and 109 control females; 82 MS males and 94 control males). The tissue-specific meta-analysis identified the overexpression of KIR2DL3 in blood in females and 13 genes with a sex-based differential expression pattern in the nervous system (7 overexpressed in females: ARL17B, CECR7, CEP78, STMP1, TRAF3IP2-AS1, ZNF117 and ZNF488; and 6 overexpressed in males: IFFO2, LOC401127, NUDT18, RNF10, SLC17A5, and UBXN2B). The two-tissue meta-analysis detected a single gene overexpressed in females (LOC102723701). Functional analyses revealed different altered immune scenarios in females and males. A pro-inflammatory environment and innate immune responses related to myeloid linage predominate in females, while in males, adaptative responses associated with the lymphocyte linage. Additionally, MS females displayed alterations in mitochondrial respiratory chain complexes, purine, and glutamate metabolism, while MS males displayed alterations in stress response to metal ion, amine, and amino acid transport. Conclusion We found transcriptomic and functional differences between MS males and females (especially in the immune system), which may support the development of sex-specific treatments. Our study highlights the importance of understanding sex as a variable in MS.