No independent role of the -1123 G>C and +2740 A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations

Introduction: The PTPN22 is a negative regulator of the T cell response. Its +1858C > T (R620W) polymorphism has been shown to associate with a risk for multiple autoimmune diseases, including type 1 diabetes (T1D) and juvenile idiopathic arthritis (JIA). The minor (susceptibility) allele is absent in Asian populations, but a recent study suggested an independent involvement of another polymorphism located within the promoter -1123 nucleotides relative to the translational start site. Aims: We aimed to analyse the association of three PTPN22 polymorphisms in two distinct Caucasian populations, the Czechs (with T1D and with JIA) and Azeri (with T1D). Methods: The single nucleotide polymorphisms (SNP) at positions -1123 (rs2488457), +1858 (rs2476601, the R620W substitution), and +2740 (rs1217412) were genotyped using TaqMan assays in 372 subjects with childhood-onset T1D, 130 subjects with JIA, and 400 control subjects of Czech origin, and in 160 subjects with T1D and 271 healthy controls of Azeri origin. Results: In the Czechs, all three SNPs were in a tight linkage disequlibrium, while in the Azeri, the linkage disequlibrium was limited to between the promoter and 3'-UTR polymorphism, D-1(- 1123, +2740) = 0.99, r(2) = 0.72. Haplotype reconstruction via the expectation-maximization algorithm showed in both populations that only the haplotype containing the minor (W) allele at codon 620 was associated with T1D (OR = 2.26,95% CI 1.68-3.02 in Czechs, OR = 14.8, 95% CI 2.0-651 in Azeri) or JIA (OR = 2.43, 95% CI 1.66-3.56 in Czechs). The haplotypes having the wild-type (R) allele at codon 620 and minor alleles at - 1123 and/or +2740 were neutral as to the risk of autoimmune conditions in both populations. Conclusions: In two different Caucasian populations, the Czechs and the Azeri, no independent contribution can be detected either of the - 1123 promoter SNP or the +2740 3'-UTR SNP, and only the minor allele at PTPN22 codon 620 contributes to the risk of autoimmunity. (c) 2006 Elsevier Ireland Ltd. All rights reserved.