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Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleotide polymorphisms (SNP), present in the hotspot coding/promoter regions of IL-6, −17 and −18, with RA susceptibility or severity in a larger study cohort from Pakistan together with finding clues as to how a functional SNP impacts the predisposition towards RA. TaqMan SNP genotyping approach was first used to assess IL-6 (rs1800795), IL-17 F (rs763780), IL-17A (rs2275913), and IL-18 (rs1946518) polymorphisms in 310 subjects (150 RA and 160 control). Molecular dynamic simulations (MDS) of wild- and mutant-type IL-17A with corresponding receptor were thereafter performed using AMBER-16; Chimera 1.13 was used for analyses. Our results showed the association of two SNPs, namely IL-6 − 174 G/C [allelic (OR = 0.960, 95% CI = 0.929–0.992, p =.009)] and IL-17 F 7488 T/C [allelic (OR = 0.907, 95%CI = 0.861–0.954, p =.000)] with increased RA risk in Pakistani subjects. When mapped, IL-17 F 7488 T/C was found involved in His161→Arg161 change near the C-terminus of IL-17 F. Comparative MDS revealed enhanced stability of the mutant hence advocating a potential role of IL-17F functional SNP in RA susceptibility and/or severity. This study provides a novel structural insight for SNP-derived functional mutation and its overall impact on binding with heterotrimeric receptor complex of IL-17 receptor thereby opening new avenues for understanding the biochemical basis of the disease. [ABSTRACT FROM AUTHOR]