Impact of IL-17F 7488T/C Functional Polymorphism on Progressive Rheumatoid Arthritis: Novel Insight from the Molecular Dynamic Simulations

ABSTRACT

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.

KEYWORDS:

• Rheumatoid arthritis
• autoimmune
• SNP genotyping
• molecular dynamic simulations
• pro-inflammatory interleukins

Acknowledgments

This study was supported by a grant from the Higher Education Commission, Government of Pakistan (Project No. 8488/2017). Part of this work was performed in the DMAC, DTU Lab.; authors are especially thankful to the Lab. Manager Dr Marlene Danner Dalgaard for her kind support and guidance.

Disclosure statement

The authors of the manuscript declare no conflict of interests.

Additional information

Funding

This work was supported by the Higher Education Commission, Pakistan [NRPU-8488/2017].