Djuric Tamara, Djordjevic Ana, Kuveljic Jovana, Stefanovic Milan, Dincic Evica, Kolakovic Ana, Zivkovic Maja
Laboratory for Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia.
Clinic for Neurology, Military Medical Academy, 11000 Belgrade, Serbia.
Int J Mol Sci. 2025 May 22;26(11):4986. doi: 10.3390/ijms26114986.
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 (, and ) 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 rs3176326 and rs3176336, rs111833532, rs62363242 and rs1217817 with the previously reported locus rs10191329, and rs9643199 were genotyped using TaqMan, and the HLA-DRB115:01 status was also determined. Significant association of the rare rs62363242 allele with PMS in females, independent of HLA-DRB11501, was found. The A allele-containing genotypes were associated with molecular components of iron metabolism. haplotypes were significantly associated with mRNA levels in RRMS and SPMS patients. locus rs111833532 and locus rs10191329 showed significant associations with EDSS, MSSS and gARMSS. We detected haplotypes associated with the expression of , a part of the p53-p21 axis known to affect T cell activation/proliferation. 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 rs62363242 with the course of MS remains to be validated in larger studies.
多发性硬化症（MS）是一种慢性炎症性神经退行性疾病，其进展机制尚未明确。为了应对MS的严重程度和神经功能缺损，我们分析了845例MS患者中的7种潜在功能性基因变异及其单倍型。基于我们之前对不同MS表型中与铁死亡相关基因进行靶向RNA测序的结果，我们在排名前三的差异表达基因（、和）中选择了假定的调控变异，并研究了它们与基因表达、血浆/血清参数以及疾病严重程度（扩展残疾状态量表[EDSS]、多发性硬化症严重程度评分[MSSS]、全球评估多发性硬化症严重程度量表[gARMSS]）之间的关联。该研究纳入了604例复发缓解型（RR）MS患者和241例进展型（P）MS患者。使用TaqMan对rs3176326和rs3176336、rs111833532、rs62363242和rs1217817这几个变异以及先前报道的位点rs10191329和rs9643199进行基因分型，并确定HLA - DRB115:01状态。发现罕见的rs62363242等位基因与女性的进展型MS显著相关，且独立于HLA - DRB11501。含A等位基因的基因型与铁代谢的分子成分相关。单倍型与复发缓解型MS（RRMS）和继发进展型MS（SPMS）患者中的mRNA水平显著相关。位点rs111833532和位点rs10191329与EDSS、MSSS和gARMSS显著相关。我们检测到与p53 - p21轴的一部分（已知会影响T细胞活化/增殖）的表达相关的单倍型。作为一种氧传感器和缺氧反应的关键调节因子，变异rs111833532与DYSF - ZNF638位点rs10191329一起与临床严重程度相关。rs62363242与MS病程之间新发现的、性别特异性的关联仍有待在更大规模的研究中进行验证。
