Association of genetic variant RS3176326 residing in ferroptosis-related CDKN1A with multiple sclerosis severity

Abstract

Recently, we investigated targeted expression of ferroptosis-related genes in relation to multiple sclerosis (MS) severity, as it is proposed to be one of the mechanisms that cause neurodegeneration, hallmark of progressive multiple sclerosis (MS). The upregulation of cyclin dependent kinase inhibitor 1A (CDKN1A), a gene responsible for reduction in sensitivity to ferroptosis, was found in the secondary progressive (SP) compared to relapse remitting (RR) MS patients. We aim to investigate genetic variant rs3176326 (G/A), which has been marked by an ENCODE as the most probable functional variant in this gene, in association with SP MS. The study included a total of 213 MS patients (159 RR and 54 SP) from Serbia. Diagnosis of clinically definite MS was performed according to the revised McDonald criteria. Genotyping has been performed by TaqMan® technology. We found significantly higher frequency of rare allele bearing genotypes according to dominant model (AG+AA vs. GG) in SP MS compared to RR MS patients (p=0.015). Genotypes bearing rare allele were significantly and independently associated with SP MS with an adjusted OR 2.08 (95% CI 1.10 - 3.95, p=0.02). OR was adjusted for sex and active smoking. There was no significant association with EDSS or MSSS scores (p>0.05). Our preliminary results suggest possible association of CDKN1A rs3176326 with MS severity. Further replication of the results on larger sample size and functional analysis are inevitable.