ORIGINAL RESEARCH article
Front. Genet.
Sec. Immunogenetics
Impact of rs7528684 (-169T/C) on FCRL3, FOXP3, IL-35 Gene Expression and IgG-RF Correlation: Insights into Rheumatoid Arthritis Pathogenesis
Provisionally accepted
- Vellore Institute of Technology, Vellore, India
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background: The Fc receptor-like protein 3 (FCRL3) gene encodes for a transmembrane receptor that is predominantly expressed on the surface of Regulatory T cells (Tregs). Single Nucleotide Polymorphism (SNP) rs7528684 (-169 T/C) in FCRL3 gene is hypothesised to enhance its expression, which in turn causes Tregs dysfunction, resulting in a loss of self-tolerance and diminished production of anti-inflammatory cytokines. This process triggers rapid proliferation of autoreactive T cells and other immune cells, exacerbating the progression of Rheumatoid Arthritis (RA) and other autoimmune diseases. Methods: In the current study, we screened the FCRL3 SNP rs7528684 to assess its association with RA risk in the Indian population. The screening was done using High-Resolution Melting Analysis (HRMA) and confirmed the findings via Sanger sequencing. We further analysed the impact of SNP rs7528684 on FCRL3, Forkhead Box Protein 3 (FOXP3), and Interleukin-35 (IL-35) gene expression using quantitative real-time PCR (qPCR). The gene expression correlation between FCRL3 and FOXP3 mRNA expression was analysed using Spearman's rank correlation coefficient (ρ) analysis. Concurrently, the inflammatory serological biomarkers, Immunoglobulin G Rheumatoid Factor (IgG-RF) and C-Reactive Protein (CRP), were evaluated in RA patients. Results: The FCRL3 SNP rs7528684 C/C genotype was significantly associated with an increased risk of RA in the Indian ethnicity (p = 0.0005). Furthermore, the C allele frequency was significantly elevated within the RA group (58.6 %). Similarly, RA patients carrying the C/C genotype also exhibited higher FCRL3 mRNA expression levels than controls (p = 0.0072). Additionally, FOXP3 and IL-35 mRNA expression was downregulated in RA patients carrying the C/C genotype. Furthermore, FCRL3 mRNA expression demonstrated a significant negative correlation with FOXP3 mRNA expression (Spearman ρ = - 0.5526, p = 0.0094 and R2 = 0.3052) in RA patients. The results also showed a positive correlation between C/C genotype and IgG-RF positive RA cases. Conclusion: In summary, our findings validated that the C/C genotype of FCRL3 SNP rs7528684 was strongly associated with RA in the Indian ethnicity. This genotype was characterised with positive IgG-RF, upregulated FCRL3, and downregulated FOXP3 and IL-35, a key anti-inflammatory cytokine. Concorontly, FCRL3 and FOXP3 mRNA expression levels are inversely correlated.
Keywords: FCRL3, Rs7528684, regulatory T cells, NF-κB, Foxp3, IL-35
Received: 07 Oct 2025; Accepted: 13 Nov 2025.
Copyright: © 2025 S and Muzammil.s. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Asha Devi S, ashaselvaraj74@gmail.com
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.