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

Abstract

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.

Kv1.3 Channel Up-Regulation in Peripheral Blood T Lymphocytes of Patients With Multiple Sclerosis

“…The finding of a specific Kv1.3 up-regulation in the PB T lymphocytes of patients with MS, complements a long line of evidence that strongly supports Kv1.3 channel involvement in MS pathophysiology, such as: the presence of Kv1.3 high T EM cells in the inflammatory lesions of MS brains (Rus et al, 2005); the association of a Kv1.3 gain-of-function gene polymorphism with MS severity (Lioudyno et al, 2021); the Kv1.3 up-regulation in brains of animals with experimental allergic encephalomyelitis (Bozic et al, 2018); the finding that Kv1.3 pharmacological blockade or Kv1.3 gene-silencing in animal models of MS 1) renders mice resistant to experimental allergic encephalomyelitis (Beeton et al, 2001), 2) decreases demyelination (Murray et al, 2015), and 3) drives T cells toward an immune-regulatory phenotype (Gocke et al, 2012).…”

“…It could represent a disease stage-specific enhancement in the functional expression of Kv1.3 channels due to different levels of systemic immune activation; interestingly it has been reported that SPMS T lymphocytes show significantly reduced Fas-mediated apoptosis compared to RRMS ( Comi et al, 2000 ), a finding that could be accounted for by the enhanced Kv1.3 channel expression in SPMS. Alternatively, based on a recent genetic study that as aforementioned, associates a gain-of-function Kv1.3 gene polymorphism to a more aggressive disease course ( Lioudyno et al, 2021 ), one may propose that the higher Kv1.3 expression in the SPMS group could merely reflect a history of more active disease tending to progress to the SPMS phenotype with a higher frequency.…”

“…The role of Kv1.3 channels in MS is further strengthened by reports showing that Kv1.3-selective blockers ( Beeton et al, 2001 ; Beeton et al, 2006 ) and genetic knockout of Kv1.3 ( Gocke et al, 2012 ), ameliorate disease in animal models of multiple sclerosis. Furthermore, a recent genetic study ( Lioudyno et al, 2021 ) identified a link between a gain-of-function polymorphic allele of the Kv1.3 gene and rapid disease progression, more severe disease phenotype and increased PB CXCR3 + T EM cells in MS patients.…”

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

“…Pathways include immune system [83], adaptive immune system [84], neutrophil degranulation [85], cytokine signaling in immune system [86] and GPCR ligand binding [87] were responsible for progression of COVID-19 infection. A previous study demonstrated that the expression levels of AHSP (alpha hemoglobin stabilizing protein) [88], IL7R [89], FBXO7 [90], KLRB1 [91], PIP4K2A [92], NFE2 [93], CCR2 [94], CLEC12A [95], NLRP12 [96], PECAM1 [97], TRIM10 [98], ICAM3 [99], EEF1A1 [100], CCR4 [101], PTPRC (protein tyrosine phosphatase receptor type C) [102], CX3CR1 [103], TSPAN32 [104], EOMES (eomesodermin) [105], ATM (ATM serine/threonine kinase) [106], CD28 [107], LRRK2 [108], CCL5 [109], CD33 [110], FCRL3 [111], CCR3 [112], FGL2 [113], GZMA (granzyme A) [114], PICALM (phosphatidylinositol binding clathrin assembly protein) [115], ALOX5 [116], MME (membrane metalloendopeptidase) [117], VIM (vimentin) [118], CD93 [119], GCA (grancalcin) [120], CD226 [121], CD1D [122], TNFSF4 [123], LEF1 [124], TLR4 [125], CCR7 [126], DPP4 [127], NLRC4 [128], ITGB3 [129], RASGRP1 [130], TLR2 [131], DOCK2 [132], CSF1R [133], PRKCB (protein kinase C beta) [134], CAMK4 [135], CXCL5 [136], CD36 [137], P2RY12 [138], LILRB2 [139], CD5 [140], SLC25A37 [141], ADIPOR1 [142], PECAM1 [143], RGS10 [144], RGS18 [145], ANK1 [146], RNF182 [147], NPRL3 [148], NINJ2 [149], KCNA3 [150], ABCG2 [151], MS4A6A [152], WDR45 [153], RAB39B...…”

Recent Advances in Nanomedicines for Multiple Sclerosis Therapy

“…Since Jean Martin Charcot first described MS in 1868, many studies have been conducted to unveil the pathogeny, pathology, and mechanism of MS so as to identify effective means for treating this disease. It has been reported that both environmental and genetic factors and the gene–environment interactions would contribute to the occurrence of MS. − But which of these factors playing the most critical part in inducing MS still remains unknown. The most questionable is the pathological definition of MS.…”