Due to the complex multigenic nature of rheumatoid arthritis (RA) identification of RA susceptibility and severity genes appears to be more challenging than originally anticipated. Among many recently reported RA susceptibility genes, a missense single nucleotide polymorphism in the protein tyrosine phosphatase PTPN22 appears to be involved in susceptibility to multiple autoimmune diseases including diabetes, systemic lupus erythematosus and Graves disease. Whether this polymorphism is also associated with severity of the phenotype in diseased individuals is not known. PTPN22 encodes a hematapoetic phosphatase also known as Lyp that functions as a negative regulator of T-cell activation via interaction with the c-Src tyrosine kinase Csk and phosphorylation of regulatory tyrosines or other Src family kinases, such as Lck and Zap70. The R620W polymorphism results in substitution of conserved arginine with tryptophan in the proximal SHH-3 binding domain of PTPN22, which is necessary for interaction with Csk. In vitro experiments show that the W620 variant of PTPN22 binds less efficiently to Csk, suggesting T cells expressing this allele may be hyper-responsive and more prone to autoimmunity.
To investigate the association of R620W polymorphism with RA in a Dutch Caucasian population and to determine whether this polymorphism associates with a qualitative phenotype of RA (remission versus progression) or a quantitative phenotype (rate of joint damage).
PTPN22 genotyping was performed on DNA from 425 RA and 343 undifferentiated arthritis patients participating in the Leiden Early Arthritis Clinic and over 200 control individuals, both of Dutch Caucasian origin. Samples were genotyped using allele-specific kinetic PCR. Disease features were measured as previously published. X-rays were scored every year.
We confirmed association of the R620W allele of PTPN22 polymorphism with RA in our Dutch Caucasian population. Minor allele frequencies of 0.07 and 0.12 were found in controls and cases, respectively, with P = 0.008 and an allelic odds ratio of 1.91, 95% confidence interval = 1.18–3.11. Surprisingly PTPN22 appeared to be a susceptibility gene for undifferentiated arthritis that either progresses or does not progress to RA. PTPN22 status did not influence the disease persistency, as analyzed in the remission versus non-remission group, or the disease severity as determined by analysis of joint damage.
Our results suggest that the R620W allele of PTPN22 increases susceptibility to RA but does not confer risk to a more severe disease course either with respect to joint destruction or with respect to disease severity.
Figure 1. Progression of joint damage (Sharp–van der Heijde units).