PTPN22
Protein tyrosine phosphatase, non-receptor type 22
Gene Number: 26191
Location: 1p13.2
Key Functions: T-cell receptor signaling regulation, immune tolerance, autoimmunity susceptibility, inflammatory response control
PTPN22 encodes protein tyrosine phosphatase non-receptor type 22 (PTPN22), a cytoplasmic enzyme that serves as a negative regulator of T-cell activation and immune signaling. It plays an essential role in maintaining immune homeostasis by fine-tuning the threshold of T-cell receptor (TCR) activation and ensuring self-tolerance. PTPN22 is predominantly expressed in hematopoietic cells, including T lymphocytes, B cells, and macrophages, where it acts as a key intracellular checkpoint to prevent inappropriate or excessive immune activation.
Genetic variation in PTPN22 has profound implications for immune regulation and disease susceptibility. The most studied polymorphism, R620W (rs2476601), results in an arginine-to-tryptophan substitution that disrupts the interaction between PTPN22 and Csk, weakening the inhibitory signaling complex. This leads to enhanced T-cell reactivity, a lower threshold for immune activation, and impaired deletion of autoreactive clones during immune development.
The R620W variant has been robustly associated with increased risk for a wide range of autoimmune diseases, including:
Type 1 diabetes mellitus (T1D)
Rheumatoid arthritis (RA)
Systemic lupus erythematosus (SLE)
Graves’ disease
Hashimoto’s thyroiditis
Vitiligo
Addison’s disease
These associations reflect the critical role of PTPN22 in maintaining the balance between immune responsiveness and tolerance. Carriers of the risk allele exhibit heightened autoimmune reactivity due to altered phosphatase regulation, contributing to the breakdown of self-tolerance and chronic inflammation.
SNP ID | Your Genotype | Alternative Alleles | Interpretation |
|---|---|---|---|
rs2476601 | Analyze your DNA to see your genotype | G | Analyze your DNA to see a personalized result. |
rs33996649 | Analyze your DNA to see your genotype | T | Analyze your DNA to see a personalized result. |
rs2476601
GG – Normal risk for autoimmune diseases (R).
AG – ~2× higher risk of rheumatoid arthritis and other autoimmune disorders (R).
AA – ~3.2× higher risk of rheumatoid arthritis and multiple autoimmune diseases (R).
Functional effect: The A allele (1858T, R620W) is a gain-of-function variant that disrupts TCR signaling by enhancing phosphatase activity, increasing autoimmunity risk.
rs33996649
CC – Normal risk for autoimmune diseases (R).
CT – Slightly lower risk for several autoimmune conditions, including Crohn’s disease, ulcerative colitis, and rheumatoid arthritis (R).
TT – Likely lower risk, though evidence is limited (R).
Functional effect: The A allele (R263Q) is a loss-of-function change impairing phosphatase activity in the catalytic domain, and may modestly reduce autoimmune susceptibility.
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