Association of Functional Gene Variants in DYSF–ZNF638, MTSS1 and Ferroptosis-Related Genes with Multiple Sclerosis Severity and Target Gene Expression

Abstract

Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants and their haplotypes in 845 MS patients. Based on our previous results of targeted RNAseq on ferroptosis-related genes in distinctive MS phenotypes, we selected putative regulatory variants in the top three DEGs (CDKN1A, MAP1B and EGLN2) and investigated their association with gene expression, plasma/serum parameters and disease severity (EDSS, MSSS, gARMSS). The study included 604 patients with relapsing–remitting (RR) and 241 with progressive (P) MS. The variants CDKN1A rs3176326 and rs3176336, EGLN2 rs111833532, MAP1B rs62363242 and rs1217817 with the previously reported DYSF-ZNF638 locus rs10191329, and MTSS1 rs9643199 were genotyped using TaqMan®, and the HLA-DRB1*15:01 status was also determined. Significant association of the rare MAP1B rs62363242 allele with PMS in females, independent of HLA-DRB1*1501, was found. The A allele-containing genotypes were associated with molecular components of iron metabolism. CDKN1A haplotypes were significantly associated with CDKN1A mRNA levels in RRMS and SPMS patients. RAB4B-EGLN2 locus rs111833532 and DYSF-ZNF638 locus rs10191329 showed significant associations with EDSS, MSSS and gARMSS. We detected haplotypes associated with the expression of CDKN1A, a part of the p53-p21 axis known to affect T cell activation/proliferation. RAB4B-EGLN2, an oxygen sensor and critical regulator of the response to hypoxia, variant rs111833532, along with DYSF-ZNF638 locus rs10191329, was associated with clinical severity. The indicated, novel, sex-specific association of MAP1B rs62363242 with the course of MS remains to be validated in larger studies. © 2025 by the authors.