Association of FCRL3 gene variants with rheumatoid arthritis susceptibility in the indian population: a combined case-control and in- silico analysis

Background Rheumatoid Arthritis (RA) is characterized as a systemic, chronic inflammatory autoimmune condition that causes joints damage and bone deformities. Recent studies indicate that the Single Nucleotide Polymorphisms (SNPs) within the immunoregulatory genes like Fc receptor-like3 ( FCRL3 ) have a significant association with RA. The primary objective of this study is to explore the association between FCRL3 gene variants and RA risk in 226 Indian RA patients compared to 239 controls. Methods Genotyping of FCRL3 SNPs rs7522061, rs11264799, rs11264797, and rs7549100 was performed using High-Resolution Melting Analysis, followed by Sanger sequencing to validate the accuracy of the results. To assess the association between SNPs and RA, unadjusted odd ratios (ORs) with 95% Confidence Interval (CI), gender-stratified analyses, and multivariable logistic regression adjusted for age and sex were performed. Furthermore, to investigate the impact of rs7522061 SNP in RA pathogenesis, an in silico approach involving homology modelling and molecular docking (HADDOCK) of FCRL3 wild type vs. variant (N28D) protein with SHP-1 was employed and 1,000 ns?Coarse-Grained Molecular Dynamics (CG-MD) simulations (GROMACS/MARTINI v3.0) was performed. Results The rs7522061 G/A genotype was significantly associated with increased RA risk (unadjusted OR = 1.84, 95% CI = 1.21–2.79, adjusted p = 0.0200). Multivariable logistic regression confirmed this association was independent of age and sex (adjusted OR = 2.03, p = 0.0028). In-silico analysis revealed that the FCRL3 N28D variant formed a more favourable docking interface with SHP-1 (mean HADDOCK score: 61.1 ± 11.0 vs. - 53.45 ± 5.84) compared to wild type and 1,000 ns CG-MD stimulation exhibited faster equilibration, lower RMSD, tighter Interfacial distance (0.15 nm), more persistent interprotein contacts, and greater compactness. Conclusion FCRL3 SNP rs7522061 G/A genotype contributes to RA susceptibility in the Indian population. The computational study suggests that the N28D substitution enhances FCRL3–SHP-1 complex stability, which may disrupt Treg function through increased negative signalling.