ASSOCIATION OF FUNCTIONAL POLYMORPHISMS OF PTPN22 AND TP53 IN CAUCASIAN PSA POPULATION

Background: The PTPN22 gene encodes a functional protein tyrosine phosphatase known as lymphoid phosphatase which acts as a regulator of the negative regulatory kinase cytosine tyrosine kinases in T cells, and may play a role in suppression of T-cell activation. A functional SNP at nucleotide position 1858 (rs2476601) causing an Arg→Trp substitution which disrupts the binding site for the negative regulatory kinase CSK was recently found to be associated with Type-1 Diabetes (Bottini et al., 2004), and subsequently associations have been shown with other autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) in Caucasian populations.The p53 protein has long been known to be related to the regulation of cell growth and prevention of carcinogenesis. Recently, it has been shown that tp53 was consistently underexpressed in the autoimmune conditions RA, SLE, MS, and IDDM (Olsen et al., 2004), and also that cellular damage response pathways that are dependent on p53 aredefective in patients with RA (Mass et al. 2003) A functional variant of p53 (Pro72Arg, rs1042522) has been shown to induce apoptosis markedly better than the wild-type variant, and has been associated Juvenile Chronic Arthritis (JCA) but not adult onset RA.Objectives: Given the implication of both PTPN22 and tp53 in multiple autoimmune disorders, we examined the association of these two functional SNPs, in our Caucasian psoriatic arthritis (PsA) population.Methods: All patients with PsA had inflammatory arthritis in the presence of psoriasis. All controls were ethnically matched and had no evidence of any autoimmune disease. All primers were designed using Sequenom SpectroDESIGNER software, scanned using a mass spectrometry workstation (Bruker), and analyzed using the Sequenom SpectroTYPER-RT softwareResults: 238 PsA patients and 149 controls were genotyped for PTPN22 (rs2476601). The G/G; G/A and A/A genotypes for cases and controls was 191, 44, 3 vs 121, 25, 3 respectively. There was no difference in the minor allele (A) frequency for PTPN22; 10.5 vs 10.4% respectively, p=0.96 [95% CI (0.7 – 1.5)]. 217 PsA patients and 148 controls were genotyped for tp53 (rs1042522). The G/G; G/C and C/C genotypes for cases and controls was 119, 87, 11 vs 78, 60, 10 respectively. There was no difference in the minor allele (C) frequency for tp53; 25.1 vs 27.0% respectively, p =0.56 [95% CI (0.7 – 1.2)].Conclusion: The first study to assess the association of PTPN22 and tp53 and PsA, failed to implicated these high priority candidate genes in our Caucasian PsA population. Based on theconflicting published data regarding the role of these genes in autoimmune disease, we recommend further studies to more definitively elucidate their role.References: 1. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004; 36(4): 337-8.2. Olsen NJ, Moore JH, Aune TM. Gene expression signatures for autoimmune disease in peripheral blood mononuclear cells. Arthritis Res Ther. 2004; 6(3): 120-8.3. Maas KH, Westfall M, Pietenpol J, Olsen N, Aune T: Cellular damage response defects in human rheumatoid arthritis. Arthritis Rheum 2003, 48:277.Citation: Ann Rheum Dis, volume 64, supplement III, year 2005, page 117Session: Genomics, genetics basis of disease and HLA/T cell recognition