Extended report The PTPN22*C1858T functional polymorphism is associated with susceptibility to inflammatory polyarthritis but neither this nor other variants spanning the gene is associated with disease outcome H Naseem, W Thomson, A Silman, J Worthington, D Symmons, A Barton ARC Epidemiology Unit, University of Manchester, UK Correspondence to: A Barton ARC Epidemiology Unit, University of Manchester, Oxford Road, Manchester, M13 9PT, UK; anne.barton@ manchester.ac.uk Accepted 1 July 2007 Published Online First 31 July 2007 This paper is freely available online under the BMJ Journals unlocked scheme, see http:// ard.bmj.com/info/unlocked.dtl ABSTRACT Background: The PTPN22 gene has been widely confirmed as a susceptibility gene for rheumatoid arthritis (RA) in populations of Northern European descent. The aim of the current study was to explore the role of variants spanning the PTPN22 gene in determining susceptibility to and outcome of inflammatory polyarthritis (IP). Patients and methods: Single nucleotide polymorphism (SNP) variants spanning the gene were genotyped using the Sequenom MassArray platform and tested, firstly for their association with susceptibility to IP. Genotype frequencies were compared between new onset IP cases (n = 843) and population controls (n = 471). Secondly, a within-cohort analysis was performed testing each variant for association with a number of clinical outcome measures reflecting disease severity including radiological erosions, physical function, measured using the Health Assessment Questionnaire (HAQ) score, and disease activity at defined time-points following disease pre- sentation. Results: A significant association between carriage of the PTPN22*1858T allele and IP (odds ratio (OR) = 1.4 (95% CI 1.1–1.9), p = 0.02) was observed. The strength of the effect was similar in the RA subgroup (OR = 1.4 (95% CI 1.0–1.9), p = 0.05). No association between IP susceptibility and any of the other SNPs was detected. No association was detected for any of the SNPs tested, including the PTPN22*C1858T polymorphism, for either erosive status, Larsen score by 5 years or other markers of clinical outcome. Conclusion: The PTPN22*C1858T polymorphism is associated with susceptibility to IP, but we have found no evidence for association of this or other variants spanning the gene with clinical outcome measures. A considerable genetic contribution to rheumatoid arthritis (RA) is demonstrated by both twin and family studies.1 The strongest association to date has been found with the HLA-DRB1 gene and, in particular, with alleles that code for a consensus amino acid sequence within the third hypervariable region of the DRB1 chain (the shared-epitope). More recently, progress has been made in identify- ing other RA susceptibility genes (reviewed in Orozco et al).2 The most convincing association has been demonstrated with a functional single nucleotide polymorphism (SNP) mapping to the lymphoid tyrosine phosphatase, PTPN22, gene (PTPN22*C1858T).3 This finding has been widely and consistently replicated in populations of Northern European descent.4 The PTPN22 gene maps to chromosome 1p13 and codes for a tyrosine phosphatase that is involved in immune regulation as a negative regulator of T cell activity. The polymorphism results in the substitution of the wild-type, arginine, with a variant, tryptophan, amino acid at codon 620 (R620W). Recent work suggests that the polymorphism may lead to a ‘‘gain-of-func- tion’’ as the protein has been shown to be changed into a more active tyrosine phosphatase in the presence of the tryptophan variant.5 It is hypothe- sised that reduced T-cell signalling may occur as a result and, in turn, this may enable auto-reactive T cells to escape deletion during thymic selection and thus persist in the circulation to become activated at a later stage. Although the primary association is with the PTPN22*C1858T polymorphism, evidence for independent association of three other SNPs mapping within the gene with susceptibility to RA has since been reported but this finding has not been replicated in two subsequent studies.6–8 In the clinical setting, the greatest utility for genetic markers would be if they led to the identification of a marker that could predict, at the earliest stages of inflammatory polyarthritis (IP), which patients will proceed to develop more severe disease. This could help to identify a subgroup of patients that could be targeted for aggressive therapy, while sparing those least likely to develop severe disease from the potential side effects associated with such drug therapy. While both the shared epitope and the PTPN22*C1858T allele are certainly associated with RA, the ques- tion of whether these associations are primarily with susceptibility or severity has proved difficult to determine because many previous studies have investigated cross-sectional series of hospital-based cases that often represent the severe end of the spectrum of disease. Ideally, such studies should be performed in inception cohorts of patients fol- lowed prospectively. In an unselected series of patients presenting to primary care with early IP and followed prospectively as part of the Norfolk Arthritis Register (NOAR), we have previously shown that the shared epitope is more strongly associated with severity markers such as radiologi- cal erosions than with susceptibility.9 251 Ann Rheum Dis 2008;67:251–255. doi:10.1136/ard.2007.071894