IL-21 rs2055979 and serum IL-21 levels are associated with both non-segmental and segmental vitiligo in an Iranian cohort

BACKGROUND: Vitiligo is an autoimmune disorder primarily categorized into non-segmental (NSV) and segmental (SV) subtypes. Interleukin-21 (IL-21) is a pleiotropic cytokine implicated in immune dysregulation. OBJECTIVE: To investigate the association of serum IL-21 levels and two genetic variants (rs2055979 and rs4833837) with susceptibility to NSV and SV in an Iranian cohort. METHODS: The study included 264 vitiligo patients (225 NSV, 39 SV) and up to 390 healthy controls. Serum IL-21 was measured by ELISA. Genotyping for rs2055979 was performed by RFLP-PCR, and for rs4833837 by ASO-PCR. RESULTS: Serum IL-21 levels were significantly elevated in both NSV (median 71.50 pg/mL) and SV (median 65.35 pg/mL) patients compared to controls (median 18.70 pg/mL; p < 0.0001). For rs2055979, the GT genotype was associated with increased risk of NSV (unadjusted OR = 2.99, 95% CI = 1.86-4.80, p < 0.0001; age- and sex-adjusted OR = 1.809, 95% CI = 1.061-3.085, p = 0.029) and SV (unadjusted OR = 4.29, 95% CI = 1.45-12.7, p = 0.005; adjusted OR = 3.486, 95% CI = 1.006-12.077, p = 0.049). The unadjusted G allele was a risk factor for NSV (OR = 1.52, 95% CI = 1.19-1.94, p = 0.0009) but not for SV (p = 0.09). The GG genotype also conferred elevated unadjusted risk for NSV (OR = 2.51, 95% CI = 1.44-4.37, p = 0.0009). In contrast, rs4833837 showed no significant association with either vitiligo subtype. CONCLUSION: The IL-21 rs2055979 polymorphism is associated with vitiligo susceptibility, with the GT genotype representing a risk factor for both NSV and SV after adjustment for age and sex. The marked elevation of serum IL-21 in both NSV and SV further supports a pathogenic role for IL-21, suggesting the IL-21/IL-21R axis as a potential therapeutic target.