rs2476601 — PTPN22 R620W

PTPN22 R620W — The Master Autoimmune Switch

The PTPN22 gene encodes lymphoid tyrosine phosphatase (LYP), a critical brake on T-cell and B-cell activation. This enzyme acts as a master regulator of immune signaling, dephosphorylating key proteins¹¹ dephosphorylating key proteins
PTPN22 dephosphorylates LCK and ZAP70, critical kinases in the T-cell receptor signaling cascade in the T-cell receptor pathway to prevent overactivation. The R620W variant (also designated C1858T) changes arginine to tryptophan at position 620, disrupting the protein's interaction²² disrupting the protein's interaction
The R620W substitution disrupts binding between PTPN22 and CSK kinase in the P1 proline-rich motif with its partner kinase CSK. This single amino acid change has emerged as the strongest non-HLA genetic risk factor³³ strongest non-HLA genetic risk factor
PTPN22 is the most influential non-major histocompatibility complex gene to promote autoimmunity for autoimmune disease.

The Mechanism

PTPN22 normally functions as a negative regulator of T-cell receptor signaling. The protein contains a catalytic phosphatase domain at the N-terminus and four proline-rich motifs (P1-P4) at the C-terminus. The R620W variant sits within the P1 motif, which mediates binding to CSK. Biochemical studies demonstrate⁴⁴ Biochemical studies demonstrate
R620W is a gain-of-function variant showing increased phosphatase activity and reduced Lck phosphorylation feedback regulation that the variant exhibits enhanced phosphatase activity while losing normal regulatory feedback. The disrupted PTPN22-CSK interaction impairs phosphorylation of PTPN22 at Y536, removing an inhibitory mechanism⁵⁵ removing an inhibitory mechanism
Y536 phosphorylation normally inhibits PTPN22 activity; R620W reduces this phosphorylation, creating sustained inhibition that normally dampens the phosphatase. The net effect is a gain-of-function variant that excessively inhibits T-cell signaling⁶⁶ excessively inhibits T-cell signaling
The R620W variant creates gain-of-function inhibition of TCR signaling particularly affecting low-avidity T cell responses—but paradoxically increases autoimmune risk.

The mechanism explains this apparent paradox: PTPN22 R620W preferentially affects responses to low-avidity antigens⁷⁷ preferentially affects responses to low-avidity antigens
Loss of PTPN22 function selectively impacts T-cell responses to weak self-antigens but not high-avidity antigens—precisely the type of self-antigens that should trigger tolerance. Gene editing studies in human T cells⁸⁸ Gene editing studies in human T cells
CRISPR-engineered R620W variant in human cord blood T cells showed enhanced proliferation and Th1 skewing with low-avidity self-reactive TCRs confirm that the variant permits increased activation of weakly self-reactive T cells, potentially expanding the self-reactive T-cell pool and skewing toward inflammatory phenotypes. This allows mildly autoreactive T cells to escape negative selection, setting the stage for autoimmune attack.

The Evidence

PTPN22 R620W was first associated with type 1 diabetes in 2004⁹⁹ first associated with type 1 diabetes in 2004
Initial discovery linked R620W to type 1 diabetes with consistent replication across multiple populations, rapidly followed by associations with rheumatoid arthritis and systemic lupus erythematosus. A meta-analysis of rheumatoid arthritis¹⁰¹⁰ meta-analysis of rheumatoid arthritis
Study of 1,413 cases found OR=1.75 for RF-positive RA; homozygotes showed OR=4.57, more than doubling disease risk found odds ratios of 1.75 for heterozygotes and 4.57 for homozygotes—a clear dose-dependent effect. The variant shows an additive inheritance pattern¹¹¹¹ additive inheritance pattern
Meta-analysis supported additive rather than dominant effect on type 1 diabetes risk, with each copy incrementally increasing risk.

The variant displays marked population stratification¹²¹² marked population stratification
1858T allele frequency is ~7% in Europeans, ~1% in Asians, extremely rare in Africans: approximately 7% allele frequency in European populations, 1-2% in Asian populations, and near-absent in African populations. This distribution explains why autoimmune disease associations were first identified in European cohorts. Diseases with documented R620W associations¹³¹³ documented R620W associations
PTPN22 R620W associated with RA, T1D, SLE, Graves' disease, vitiligo, alopecia areata, celiac disease, and myasthenia gravis include rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, Graves' disease, vitiligo, alopecia areata, celiac disease, and myasthenia gravis. Notably, the variant shows no association¹⁴¹⁴ the variant shows no association
No association detected with multiple sclerosis or inflammatory bowel disease with multiple sclerosis or inflammatory bowel disease, suggesting specificity for antibody-mediated autoimmune conditions.

Recent cross-trait meta-analyses¹⁵¹⁵ Recent cross-trait meta-analyses
rs2476601-A identified as shared risk locus between vitiligo and alopecia areata in GWAS meta-analysis identified rs2476601 as a shared risk locus between vitiligo and alopecia areata, autoimmune skin conditions affecting melanocytes and hair follicles. A meta-analysis specific to alopecia¹⁶¹⁶ meta-analysis specific to alopecia
Systematic review found T allele significantly correlated with AA susceptibility; C allele protective found the T (risk) allele significantly correlated with alopecia areata susceptibility while the C allele was protective.

Practical Implications

If you carry one or two copies of the risk allele (AG or AA genotype), you have elevated baseline risk for multiple autoimmune conditions. This doesn't mean you'll develop these diseases—most carriers remain healthy—but awareness enables proactive monitoring and early intervention. The risk is highest for seropositive disease¹⁷¹⁷ risk is highest for seropositive disease
PTPN22 association strongest with RF-positive RA and antibody-positive autoimmunity forms characterized by autoantibody production (RF-positive rheumatoid arthritis, anti-thyroid antibodies in Graves' disease, anti-dsDNA in lupus).

Pay attention to early warning signs of autoimmune disease: unexplained joint pain or swelling, chronic fatigue, skin changes including vitiligo patches or patchy hair loss, thyroid dysfunction symptoms, or recurrent inflammatory episodes. If you develop one autoimmune condition, your risk for additional autoimmune diseases is elevated—PTPN22 R620W predisposes to clustering of autoimmune conditions¹⁸¹⁸ clustering of autoimmune conditions
Risk from 1858T allele increased in patients with family history of other autoimmune diseases within individuals and families.

For women planning pregnancy, note that autoimmune diseases often flare postpartum due to immune system rebound. Pregnancy with known PTPN22 risk alleles warrants closer monitoring by rheumatology or immunology specialists. If you have family history of autoimmune disease combined with R620W carrier status, consider baseline autoantibody screening (ANA panel, RF, anti-TPO, anti-CCP depending on symptoms) to catch subclinical autoimmunity.

Interactions

PTPN22 R620W interacts with HLA haplotypes—the strongest autoimmune risk factors—in a synergistic rather than additive manner. Studies show no genetic epistasis¹⁹¹⁹ Studies show no genetic epistasis
No evidence of genetic association between PTPN22 and HLA susceptibility alleles in rheumatoid arthritis between PTPN22 and HLA-DR shared epitope alleles in rheumatoid arthritis, suggesting independent but convergent mechanisms. However, the combination of PTPN22 risk variant with high-risk HLA haplotypes²⁰²⁰ combination of PTPN22 risk variant with high-risk HLA haplotypes
PTPN22 T/T and C/T genotypes more frequent in T1D cases without high-risk HLA DR3/4-DQ8 (HLA-DR3/4-DQ8 for type 1 diabetes, HLA-DRB1 shared epitope for RA) substantially elevates absolute disease risk beyond what either confers alone.

Within the PTPN22 locus, multiple SNPs contribute to risk²¹²¹ multiple SNPs contribute to risk
Two SNPs (rs3811021, rs3789605) on separate haplotype associated with RA independent of R620W. Haplotype analysis shows rs2476601 interacts with rs1310182 and rs3789604: the minor allele of rs3789604 amplifies R620W risk²²²² minor allele of rs3789604 amplifies R620W risk
rs3789604 minor allele increased R620W OR to 2.53 for homozygotes and 1.77 for heterozygotes, while rs1310182 minor allele modestly reduces it. These haplotype effects underscore that R620W, while the primary driver, doesn't fully account for PTPN22's autoimmune associations.

In vitiligo and alopecia areata, PTPN22 R620W combines with HLA class II variants²³²³ PTPN22 R620W combines with HLA class II variants
Shared genetic architecture includes rs2476601-A plus HLA-DRB6, HLA-DQA2, HLA-DRB1, and HLA-DQA1 variants to create compound autoimmune risk affecting skin pigmentation and hair follicles.