{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:48:12Z","timestamp":1791244092493,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Protein Tyrosine Phosphatase Non-Receptor Type 22 (<jats:italic>PTPN22<\/jats:italic>) gene encodes for Lymphoid-Specific Tyrosine Phosphatase (LYP), predominantly expressed in T lymphocytes to regulate the immune responses by modulating T-cell proliferation and activation. Single Nucleotide Polymorphisms (SNPs) in <jats:italic>PTPN22<\/jats:italic> alter the structure and function of LYP, leading to dysregulation of T-cell response and increasing the risk for autoimmune disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To investigate the intricate relationships between <jats:italic>PTPN22<\/jats:italic> SNPs rs2476601, rs2488457, and rs33996649 and Rheumatoid Arthritis (RA) pathogenesis, genotyping was accomplished using High-Resolution Melting Analysis (HRMA) and Sanger sequencing in 229 RA and 239 control samples. The SNP rs2476601 disrupts the interaction between PTPN22 and Peptidyl arginine deiminase, which leads to an altered production of citrullinated proteins and consequently raises anti-CCP autoantibody levels. Hence, we further analyzed the impact of SNP rs2476601 on serum anti-CCP antibody levels in RA patients, and structural difference between the PTPN22 wild and R620W variant proteins by Molecular Dynamics Simulation (MDS). We also investigated the <jats:italic>PTPN22<\/jats:italic> rs2488457 variant\u2019s effect on <jats:italic>PTPN22<\/jats:italic> mRNA expression level, noting its location in the gene\u2019s promoter region, which may affect transcription and expression level. The influence of rs2488457 on <jats:italic>PTPN22<\/jats:italic> mRNA expression level was determined by comparative threshold cycle method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The statistical analysis confirms that RA samples with SNP rs2476601 C\/T genotype (Odds Ratio (OR)\u202f=\u202f3.6136; Confidence Interval (CI)\u202f=\u202f2.2789 to 5.7300; <jats:italic>p<\/jats:italic>\u202f=\u202f0.0001) and rs2488457 C\/C genotype (OR\u202f=\u202f1.5179; CI\u202f=\u202f1.0453 to 2.2042; <jats:italic>p<\/jats:italic>\u202f=\u202f0.0283) were associated with RA. SNP rs2476601 C\/T genotype also elevated the serum anti-CCP antibody levels significantly (<jats:italic>p<\/jats:italic>\u202f=\u202f0.01). The MDS result revealed significant structural and dynamic differences between wild and R620W variant forms of the PTPN22 protein. Furthermore, individuals with RA carrying the C\/C genotype at the rs2488457 locus significantly (<jats:italic>p<\/jats:italic>\u202f=\u202f0.0350) downregulated the <jats:italic>PTPN22<\/jats:italic> mRNA expression level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study suggests that <jats:italic>PTPN22<\/jats:italic> SNPs rs2476601, rs2488457 are strongly linked with RA susceptibility in the Indian ethnicity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1688505","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T05:36:37Z","timestamp":1761024997000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the impact of SNPs rs2476601, rs2488457, and rs33996649 on PTPN22 expression, structure, and anti-CCP level in rheumatoid arthritis of the Indian population: a case-control and computational study"],"prefix":"10.3389","volume":"12","author":[{"given":"S.","family":"Aswini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Asha Devi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1097\/01.rhu.0000166673.34461.33","article-title":"Immunologic mechanisms in the pathogenesis of rheumatoid arthritis","volume":"11","author":"Firestein","year":"2005","journal-title":"J Clin Rheumatol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/sj.gene.6363635","article-title":"Genetic analysis of multiplex rheumatoid arthritis families","volume":"1","author":"Bali","year":"1999","journal-title":"Genes 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