Differential Roles of IL-18 and IL-8 Gene Variations in Multiple Sclerosis: Associations with Susceptibility and MRI Disease Activity.

Background/Objectives: Cytokine-mediated immune dysregulation contributes to the heterogeneity of multiple sclerosis (MS). Interleukin-18 (IL-18) and interleukin-8 (IL-8) are involved in distinct inflammatory pathways; however, their genetic contributions to disease susceptibility and radiological activity remain incompletely defined. Methods: In this study, 98 relapsing-remitting MS (RRMS) patients and 98 healthy controls were genotyped for IL-18 and IL-8 variations using PCR-based methods. Clinical data and MRI findings were analyzed in the MS cohort. Associations with disease susceptibility, clinical severity (EDSS), and MRI activity were evaluated using regression analyses. Results: IL-18 (-137 G/C) and IL-8 variations were significantly associated with MS susceptibility. The G allele of IL-18 (-137), the T allele of IL-8 (-251), and the C allele of IL-8 (+781) were more frequent in MS patients. No significant associations were observed between cytokine variations and clinical severity measures. However, IL-18 (-137) variation was significantly associated with higher baseline MRI lesion burden, with C allele carriers showing increased lesion counts. In addition, IL-8 (-251 AA genotype) was independently associated with increased annual lesion development. These findings were confirmed in multivariable regression analyses. Conclusions: IL-18 and IL-8 gene variations contribute to MS through distinct but complementary mechanisms. IL-18 appears to be primarily involved in disease susceptibility and baseline inflammatory burden, whereas IL-8 is more closely associated with ongoing radiological activity. These results highlight the importance of integrating genetic and imaging biomarkers to better understand disease heterogeneity in MS.