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PTPN22 encodes the lymphoid tyrosine phosphatase Lyp, a key negative regulator of T-cell receptor signaling. The functional SNP R620W (rs2476601) has been robustly associated with systemic lupus erythematosus (SLE) in multiple populations. In an initial North American cohort of 525 independent white SLE cases versus 1,961 controls, heterozygotes exhibited an odds ratio (OR) of 1.37 and homozygotes an OR of 4.37 for SLE risk (PMID:15273934). This association has been replicated in family-based studies and extended to diverse ethnic groups.
In the Multiple Autoimmune Disease Genetics Consortium (MADGC), 265 multiplex families were genotyped for rs2476601, demonstrating cosegregation of the T allele with SLE and other core autoimmune phenotypes (PMID:15719322). Population-based and case-control studies in Colombian patients (n=143 SLE) confirmed an OR of 2.56 for the 1858T allele in SLE (PMID:16163373). A 2019 systematic review and Bayesian meta-analysis across observational and GWAS datasets reinforced the noteworthiness of the PTPN22-SLE association (PMID:30871019).
Genetically, rs2476601 is a missense variant (c.1858C>T (p.Arg620Trp)) that disrupts the P1 proline-rich motif pivotal for Csk binding. No Mendelian segregation of rare high‐penetrance variants has been reported, consistent with a polygenic risk model. The minor allele frequency ranges from ~12.7% in European-ancestry SLE cases to <1% in East Asians, highlighting ethnic heterogeneity in allele distribution and effect size.
Functional assays demonstrate that the Arg620Trp substitution alters Lyp phosphatase activity and impairs proximal TCR signaling. In healthy carriers, R620W reduces calcium mobilization, CD25 expression, and IL-10 production in CD4⁺ memory T cells and diminishes BCR-mediated proliferation (PMID:17878369, PMID:19265110). Transgenic mouse and CRISPR-edited T cell models confirm that loss of PTPN22 function leads to enhanced regulatory T cell frequencies and modulates T and B lymphocyte activation thresholds, thereby influencing autoimmunity susceptibility.
While no studies directly refute the association, ethnic-specific analyses in Japanese cohorts showed lack of polymorphism at rs2476601, indicating population-dependent risk. No rare high-penetrance SLE‐causing PTPN22 variants have been described, underscoring the variant’s moderate effect size in the polygenic context of SLE.
Integration of genetic and functional data supports a model wherein the PTPN22 R620W variant confers moderate increased risk for SLE by perturbing TCR and BCR signaling thresholds, promoting loss of tolerance. Given its reproducible effect across cohorts and mechanistic plausibility, rs2476601 genotyping can inform SLE risk stratification and guide development of Lyp-targeted immunomodulatory therapies.
Key Take-home: PTPN22 R620W (c.1858C>T (p.Arg620Trp)) is a well-validated moderate‐risk allele for SLE with defined functional consequences on lymphocyte signaling, offering utility for genetic risk assessment and therapeutic targeting.
Gene–Disease AssociationModerateMultiple large case-control (525 SLE cases vs 1,961 controls (PMID:15273934)) and family-based replication (265 multiplex families (PMID:15719322)), with meta-analysis support Genetic EvidenceModerateReproducible association of rs2476601 in >500 SLE cases and replication across populations and families Functional EvidenceModerateFunctional studies show R620W alters Lyp activity and impairs TCR/BCR signaling in human and mouse models |