Missense Mutation in the PTPN22 gene resulting in R620W change in the resulting protein LypW (normal is Lyp). Note that the (A;A) genotype is quite rare. LypW carriage is associated with diminished type I interferon (IFN) productin in response to Toll-like receptor (TLR) activation. Dysregulation of interferon, an inflammatory cytokine has been implicated in the pathogenesis of multiple autoimmune disorders including systemic lupus erythematosis (SLE).
Associated Autoimmune Disorders
[PMID 15719322] One study suggested increased risk of multiple autoimmune disorders to varying degrees:
- 2.5x risk for type-1 diabetes
- 1.5x risk for rheumatoid arthritis
- 1.5x risk for SLE
- 1.8x risk for Hashimoto thyroiditis
[PMID 21543514] Study of a very genetically homogenous population in Crete also showed association of R620W with SLE.
[PMID 22237046] [PMID 25448792] Other studies demonstrated an association of R620W with ANCA vasculitis, specifically GPA aka Wegener's and MPA, and association with increased pathology of specific organs (lung involvement, ENT involvement, skin involvement, and peripheral neuropathy were all ~1.5-2x more likely)
Ethnic Variation of Significance
[PMID 25963842] Meta-analysis showed that PTPN22 T allele resulting in R620W was significantly associated with RA in European, but not in Asian and African subjects, and failed to show any association with the presence or absence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies in those affected.