Association of IL-17 and IL-21 gene polymorphisms and haplotypes with rheumatoid arthritis susceptibility in Iraqi patients

Rheumatoid arthritis (RA) is a persistent inflammatory autoimmune disease that impacts joints and leads to gradual deterioration. Cytokines like IL-17 and IL-21 are associated with the etiology of rheumatoid arthritis due to their involvement in fostering inflammation and autoimmunity. This study investigated the association between single- nucleotide polymorphisms (SNPs) in IL-17F (rs2397084 and rs11465553) and IL-21 (rs2221903) genes and susceptibility to rheumatoid arthritis in an Iraqi cohort. The case-control study included 90 participants (50 RA patients and 40 healthy controls) from Ramadi, Al-Anbar, between November 2023 and January 2024. Genomic DNA was extracted from blood samples, and SNP genotyping was conducted using AS-PCR and ARMS-PCR techniques. Results showed a significant association between the C allele of IL-17F rs2397084 and RA susceptibility (frequency: 0.31 in patients vs. 0.16 in controls, 𝜒2 = 5.235, 𝑝 = 0.022), with genotype distributions of T/T (0.48), T/C (0.42), and C/C (0.10) in patients compared with 0.72, 0.22, and 0.05 in controls (p=0.063). The dominant model (T/C + C/C) indicated increased risk (OR=7.71, 95% CI: 1.43-41.53, p=0.008). For rs11465553, the A allele was more frequent in patients (0.38 vs. 0.06, 𝜒2 = 24.641, 𝑝 < 0.001), with genotype distributions of A/A (0.30), G/A (0.16), and G/G (0.54) in patients compared with 0.02, 0.08, and 0.90 in controls (𝜒2 = 14.881, 𝑝 = 0.001). The dominant (OR=6.28, 95% CI: 1.43- 27.60, p=0.0097) and recessive models (OR=11.64, 95% CI: 1.21-111.53, p=0.0095) confirmed this association. For IL-21 rs2221903, the T allele was more prevalent (71 in patients vs. 44 in controls,𝜒2 = 6.378, 𝑝 = 0.012), with genotype distributions of T/T (n=23), T/C (n=25), and C/C (n=2) in patients compared with T/C (n=28), C/C (n=4), and T/T (n=8) in controls (𝜒2 = 46.586, 𝑝 < 0.001). However, genetic model analysis showed no significant associations (e.g., dominant model OR=0.30, p=0.095). Deviations from Hardy-Weinberg equilibrium were observed for rs11465553 in patients (p<0.0001) and rs2221903 in controls (p=0.023), possibly reflecting disease effects or sample size limitations. These findings suggest that IL-17 and IL-21 genetic variations may contribute to RA susceptibility in the Iraqi population. Further studies in larger, multiethnic cohorts are warranted to confirm these associations and elucidate underlying mechanisms.