A common genetic variant rs2821557 in KCNA3 is linked to the severity of multiple sclerosis

• Published in: Journal of neuroscience research 2021-01, Vol.99 (1), p.200-208
• Main Authors: Lioudyno, Victoria, Abdurasulova, Irina, Negoreeva, Irina, Stoliarov, Igor, Kudriavtsev, Igor, Serebryakova, Maria, Klimenko, Victor, Lioudyno, Maria
• Format: Article
• Language: English
• Subjects: Accumulation; Alleles; autoimmunity; CCR6 protein; CD4 antigen; Chemokine receptors; CXCR3 protein; CXCR5 protein; disease progression; Flow cytometry; Gene polymorphism; Genetic diversity; Genetic variance; Genetics; Genotype & phenotype; Inflammation; Lymphocytes; Multiple sclerosis; Peripheral blood; Polymorphism; Potassium; potassium channel Kv1.3; Potassium channels (voltage-gated); Subpopulations; T lymphocytes
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.24596

The rate of symptom accumulation distinguishes between slowly and rapidly progressing forms of multiple sclerosis (MS). Given that a patient's genetics can affect the rate of disease progression, identification of genetic variants associated with rapid disease progression should provide valuable information for timely prognosis and development of optimal treatment plans. We hypothesized that the polymorphism rs2821557 in the human KCNA3 gene encoding a voltage‐gated potassium channel Kv1.3 might be one of these genetic variants, given the role of Kv1.3 in neuroinflammation, as well as the location and gain‐of‐function effect of this polymorphism. To test this hypothesis we performed an analytic study exploring the relationships between rs2821557 polymorphism and disease progression in a cohort of MS patients. The rs2821557 genotype and the rate of disease progression based on Multiple Sclerosis Severity Score (MSSS) were determined for 101 patients (68 females and 33 males). Peripheral blood CD4+ lymphocyte subpopulations (Tnaive, TCM, TEM) and the expression of chemokine receptors (CXCR5, CXCR3, CCR6, CCR4) were estimated by flow cytometry. The comparisons between groups by genotype (TT, TC, CC) and allelic approach analysis (T vs. C) revealed a significantly higher incidence of the rapid disease course (MSSS ≥ 7.5) among minor C allele carriers (CC and TC) compared to patients with the TT genotype. Furthermore, C allele carriers had higher counts of CXCR3+ TEM cells than homozygous T allele carriers. In conclusion, accelerated MS progression in C allele carriers is likely linked to enhanced Kv1.3‐mediated accumulation of pathogenic CXCR3+ TEM cells and exacerbated neuroinflammation. Case‐series study involving 101 multiple sclerosis patients revealed a link between KCNA3 polymorphism rs2821557 and the rate of disease progression. Minor C allele carriers exhibited significantly higher incidence of the rapid disease course and higher counts of CXCR3+ TEM cells compared to TT genotype carriers.