Exploring the Link Between IL-6 rs1800795 G > C SNP and the Severity of Epstein-Barr Virus-Associated Multiple Sclerosis: Potential Impact on Cognitive Impairment

Abstract

Multiple Sclerosis (MS) is a chronic immune-mediated neurological disorder frequently accompanied by cognitive impairment, which affects up to 60% of patients and is associated with faster disease progression and greater disability. Interleukin-6 (IL-6), a key proinflammatory cytokine involved in neuroinflammation, has been implicated in MS pathogenesis, and the rs1800795 (-174 G>C) single nucleotide polymorphism (SNP) in the IL6 gene may influence disease susceptibility and clinical severity. This study investigated the association between the IL6 rs1800795 polymorphism and clinical outcomes in Epstein-Barr virus (EBV)-positive MS patients, with a particular focus on cognitive dysfunction. A case-control design was employed, including 300 participants: 150 EBV-positive MS patients and 150 matched healthy controls. Genotyping was performed using TaqMan-based PCR, and clinical data such as disability status, disease progression, and cognitive performance were analyzed. The CC genotype was significantly more frequent in MS patients and was associated with a higher risk of severe disability (OR = 6.11, p = 0.0004), faster disease progression, and increased likelihood of cognitive impairment. These findings suggest that the IL6 rs1800795 polymorphism, particularly the CC genotype, contributes to MS susceptibility and adverse clinical outcomes. IL6 genotyping may hold promise as a predictive tool for disease progression and cognitive decline in EBV-associated MS, offering insights for more personalized therapeutic strategies.

Keywords: Cognitive disability; EBV; IL-6 rs1800795 G > C; Multiple sclerosis.

Fig. 1

Mechanism linking the IL-6 rs1800795 C allele to cognitive impairment in EBV-associated MS. The C allele increases IL-6 production, activates gp130 signaling, enhancing neuroinflammation, Th17 activation, B-cell survival, and blood-brain barrier disruption in EBV-associated MS. This cascade leads to the activation of microglia and astrocytes, resulting in synaptic loss and neuronal damage, particularly in brain regions critical for cognition. Consequently, C allele carriers are at greater risk for cognitive impairment, supporting its role as a genetic amplifier of neurodegeneration in MS

Fig. 2

Comparative distribution of IL6-174 G>C rs1800795 genotypes (GG, CG, CC) between healthy controls and EBV-MS patients (a); among EBV-MS patients with lower (EDSS ≤3) and higher (EDSS >3) disability scores (b); among early-based secondary progressive multiple sclerosis (EBS-MS) patients categorized by disease progression rate (c); Patients were divided into slow progressors (PI ≤ 0.2) and rapid progressors (PI > 0.2) (d); among MS patients with cognitive function >1.5 standard deviation from normal versus patients with notable cognitive dysfunction <1.5 standard deviation from normal. Data are presented as percentages of cases in each group. Statistical comparison was performed using the Chi-square test. EBV-Epstein -Barr virus, EDSS: Expanded Disability Status Scale, PI: progression index, CD: Cognitive dysfunction

Fig. 3

Forest plot displaying the odds ratios (OR) and 95% confidence intervals (CI) for the association between IL6 rs1800795 genotypes and various multiple sclerosis (MS) outcomes. Comparisons include healthy controls versus MS patients, disease severity measured by the Expanded Disability Status Scale (EDSS), disease progression rates based on progression index (PI), and cognitive dysfunction severity. The vertical dashed line at OR = 1.0 represents no association. Odds ratios greater than 1.0 indicate increased odds of the outcome in the comparison group, whereas odds ratios less than 1.0 suggest a protective effect. Statistical significance was determined using Fisher's exact test