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

Abstract

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 relative to males). The precise sex-based factors influencing risk of MS are currently unknown. Here, we explore the role of sex in MS to identify molecular mechanisms underlying observed MS sex differences that may guide novel therapeutic approaches tailored for males or females. Methods: We performed a rigorous and systematic review of genome-wide transcriptome studies of MS that included patient sex data in the Gene Expression Omnibus and ArrayExpress databases following PRISMA statement guidelines. We analyzed differential gene expression for each selected study and performed 3 meta-analyses to evaluate common features and sex bias: the first meta-analysis of 4 neurologic 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 characterize sex 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 neurologic tissue) with a total of 474 samples (189 females with MS and 109 control females; 82 males with MS and 94 control males). Blood and nervous tissue meta-analyses identified, respectively, 1 (KIR2DL3) and 13 (ARL17B, CECR7, CEP78, IFFO2, LOC401127, NUDT18, RNF10, SLC17A5, STMP1, TRAF3IP2-AS1, UBXN2B, ZNF117, ZNF488) MS-associated genes that differed between males and females. The combined-tissue meta-analysis highlighted a single RNA gene (LOC102723701) altered according to sex in MS patients. Functional analyses revealed different altered immune patterns in females and males. A pro-inflammatory environment and innate immune responses related to myeloid linage predominate in females, while in males, adaptive responses associated with the lymphocyte linage. Additionally, females with MS 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 the role of biological sex in MS.