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Association Between Multiple Sclerosis Severity and Functional Variants in Key Antioxidant Defense and
Tamara Djuric1, Jovana Kuveljic1, Ana Djordjevic1
1Laboratory for Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia.
Abstract:
Multiple sclerosis (MS) is a chronic, progressive, inflammatory neurodegenerative disease. Oxidative stress and ferroptosis are implicated in MS pathology, contributing to both inflammation and neurodegeneration. Potentially functional variants in genes related to antioxidant defense and ferroptosis were chosen through an extensive selection process to investigate their possible association with the progressive form of MS. The study included 845 MS patients (604 relapsing-remitting (RRMS) and 241 progressive (PMS)). The selected gene variants-GCLC rs572496, GCLM rs2273406, GPX4 rs713041, NQO1 rs1800566 and CAT rs2420388-were genotyped using TaqMan® technology. mRNA expression levels of the corresponding genes in PBMCs were previously determined by targeted RNA sequencing. Circulatory molecular indicators of antioxidant defense and ferroptosis were quantified using ELISA and colorimetric enzymatic recycling assays. The findings indicate that the GCLC rs572496 variant was significantly associated with MS disease severity and had a significant effect on GCLC mRNA levels. Additionally, the NQO1 rs1800566 variant had a significant effect on NQO1 mRNA expression in PBMCs of MS patients overall. The results suggest further analysis of antioxidant defense and ferroptosis-related gene variants with MS severity and validation of the gained results in larger study groups.
Insights
Genetic variants in antioxidant defense and ferroptosis pathways are linked to multiple sclerosis (MS) severity. The GCLC rs572496 variant impacts MS disease progression and GCLC mRNA levels, suggesting a role in MS pathology.
Area of Science:
- Neuroimmunology
- Genetics
- Molecular Biology
Background:
- Multiple sclerosis (MS) is a chronic, inflammatory neurodegenerative disease.
- Oxidative stress and ferroptosis are key contributors to MS pathology, driving inflammation and neurodegeneration.
- Investigating genetic variations in antioxidant and ferroptosis pathways may reveal associations with MS progression.
Purpose of the Study:
- To explore the association between specific gene variants involved in antioxidant defense and ferroptosis and the progressive form of multiple sclerosis (MS).
- To analyze the impact of these variants on gene expression and molecular indicators of oxidative stress and ferroptosis in MS patients.
Main Methods:
- Genotyping of selected variants (GCLC rs572496, GCLM rs2273406, GPX4 rs713041, NQO1 rs1800566, CAT rs2420388) in 845 MS patients using TaqMan® technology.
- Quantification of mRNA expression levels for corresponding genes in peripheral blood mononuclear cells (PBMCs).
- Measurement of circulatory molecular indicators of antioxidant defense and ferroptosis via ELISA and enzymatic assays.
Main Results:
- The GCLC rs572496 variant showed a significant association with MS disease severity and influenced GCLC mRNA levels.
- The NQO1 rs1800566 variant significantly affected NQO1 mRNA expression in the PBMCs of all MS patients studied.
- These findings highlight potential roles for specific genetic variants in MS pathogenesis.
Conclusions:
- The study identifies specific genetic variants (GCLC rs572496, NQO1 rs1800566) associated with MS severity and gene expression.
- Further research with larger cohorts is recommended to validate these findings and explore the therapeutic potential of targeting antioxidant and ferroptosis pathways in MS.
