Immune-Related Gene Variants as Modifiers of Multiple Sclerosis Severity

Kulakova, Olga; Baulina, Natalia; Kozin, Maxim; Matveeva, Natalia; Boyko, Alexey; Favorova, Olga; Kiselev, Ivan

doi:10.3390/ijms27125347

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Open AccessArticle

Immune-Related Gene Variants as Modifiers of Multiple Sclerosis Severity

by

Olga Kulakova

,

Natalia Baulina

,

Maxim Kozin

,

Natalia Matveeva

,

Alexey Boyko

,

Olga Favorova

and

Ivan Kiselev

^*

Laboratory of Medical Genomics, Pirogov Russian National Research Medical University, Moscow 117997, Russia

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(12), 5347; https://doi.org/10.3390/ijms27125347 (registering DOI)

Submission received: 8 May 2026 / Revised: 10 June 2026 / Accepted: 11 June 2026 / Published: 13 June 2026

(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)

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Abstract

Multiple sclerosis (MS) is a heterogeneous autoimmune disorder of the central nervous system of polygenic nature. Uncovering the genetic predictors of MS phenotype can help to explain the nature of the disease’s clinical heterogeneity, and contribute to the development of novel tools for precise disease prognosis. We conducted a retrospective genetic association study of 35 polymorphic variants in immune-related genes with MS severity assessed using the Multiple Sclerosis Severity Score (MSSS) in a sample of 548 Russian relapsing-onset MS patients who have not previously received immunomodulatory therapy. Variants in the CXCR5, EOMES, TNFRSF1A, IRF8, PVT1, CCR5, HLA-DRB1, IL6, TCF7, and CD40 genes were identified as MSSS-associated in at least two of the three models analyzed (MSSS > 3.5 versus ≤3.5; MSSS > 5.0 versus <2.5; MSSS as a continuous variable). Among them, variants in CCR5, HLA-DRB1 and IL6 genes were associated with MSSS only in women, while variants in the TCF7 and CD40 genes only in men. The variant in CXCR5 was MSSS-associated both in the total sample and in subgroups of female and male MS patients. Thus, we demonstrate that several GWAS-identified MS risk genes, along with other immunological loci, act as modifiers of the MS phenotype.

Keywords: multiple sclerosis; severity; MSSS; genetic polymorphism; immune-related genes; neuroinflammation

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MDPI and ACS Style

Kulakova, O.; Baulina, N.; Kozin, M.; Matveeva, N.; Boyko, A.; Favorova, O.; Kiselev, I. Immune-Related Gene Variants as Modifiers of Multiple Sclerosis Severity. Int. J. Mol. Sci. 2026, 27, 5347. https://doi.org/10.3390/ijms27125347

AMA Style

Kulakova O, Baulina N, Kozin M, Matveeva N, Boyko A, Favorova O, Kiselev I. Immune-Related Gene Variants as Modifiers of Multiple Sclerosis Severity. International Journal of Molecular Sciences. 2026; 27(12):5347. https://doi.org/10.3390/ijms27125347

Chicago/Turabian Style

Kulakova, Olga, Natalia Baulina, Maxim Kozin, Natalia Matveeva, Alexey Boyko, Olga Favorova, and Ivan Kiselev. 2026. "Immune-Related Gene Variants as Modifiers of Multiple Sclerosis Severity" International Journal of Molecular Sciences 27, no. 12: 5347. https://doi.org/10.3390/ijms27125347

APA Style

Kulakova, O., Baulina, N., Kozin, M., Matveeva, N., Boyko, A., Favorova, O., & Kiselev, I. (2026). Immune-Related Gene Variants as Modifiers of Multiple Sclerosis Severity. International Journal of Molecular Sciences, 27(12), 5347. https://doi.org/10.3390/ijms27125347

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Immune-Related Gene Variants as Modifiers of Multiple Sclerosis Severity

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