Transcriptional Signatures of Multiple Sclerosis May Explain Female-Biased Gene Expression

A recent study set out to identify transcriptional signatures in multiple sclerosis (MS) that may explain its higher prevalence in females compared to males. Current research suggests that genetic and hormonal differences contribute to the autoimmune disease's sex-based prevalence, with genes on the X chromosome potentially escaping lyonization in females, leading to increased expression of immune-regulating genes.

To explore this, researchers analyzed RNA sequencing data from 38 patients with MS and 26 age- and sex-matched controls, focusing on differential gene expression across the X chromosome and autosomes. Using custom scripts and the edgeR Bioconductor package, they identified 117 female-specific, 114 male-specific, and 66 mutual differentially expressed genes linked to MS.

The analysis revealed that female-specific genes include toll-like receptor (TLR) genes such as TLR7 and TLR8, indicating involvement in immune signaling pathways, particularly related to cytokines and interleukins. Other significant findings pointed to G protein-coupled receptor (GPCR) signaling, suggesting new therapeutic targets.

Overall, the results highlight distinct gene expression patterns associated with sex in MS, demonstrating how X-chromosomal differences contribute to varying genetic dysregulation. By identifying gene sets based on X-chromosomal composition (XX or XY), the researchers observed varying patterns of genetic dysregulation. The genes identified through this analysis may contribute to autoimmune traits, and characterizing these genetic regions offers valuable insights into the X chromosome's role in MS, according to the authors.

Reference

Gribbin J, Wolujewicz P, Soda KJ. X Chromosome analysis in multiple sclerosis for identification of genes implicated in female-biased disease presentation. Presented at: the American Academy of Neurology 2024 Annual Meeting; October 25-27, 2024; Paradise, NV; Abstract S42.007.