Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): Association between a promoter polymorphism and type 1 diabetes in Asian populations

Abstract

The protein tyrosine phosphatase, nonreceptor 22 gene (PTPN22) maps to human chromosome 1p13.3-p13.1 and encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase (Lyp). Recently, the minor allele of a single-nucleotide polymorphism (SNP) at nucleotide position 1858 (rs2476601, +1858C > T) was found to be associated with type 1 diabetes. However, the degree of the association is variable among ethnic populations, suggesting the presence of other disease-associated variants in PTPN22. To examine this possibility, we carried out a systemic search for PTPN22 using direct sequencing of PCR-amplified products in the Japanese population. Association and linkage studies were also conducted in 1,690 Japanese samples, 180 Korean samples, and 472 Caucasian samples from 95 nuclear families. We identified five novel SNPs, but not the +1858C > T SNP. Of these two frequent SNPs, -1123G > C, and +2740C > T were in strong linkage disequilibrium (LD), and the -1123G > C promoter SNP was associated with acute-onset but not slow-onset type 1 diabetes in the Japanese population (odds ratio [OR] = 1.42, 95% CI = 1.07-1.89, P = 0.015). This association was observed also in Korean patients with type 1 diabetes (Mantel-Haenszel chi2= 6.543, P = 0.0105, combined OR = 1.41 95% CI = 1.09-1.82). Furthermore, the affected family-based control (AFBAC) association test and the transmission disequilibrium analysis of multiplex families of European descent from the British Diabetes Association (BDA) Warren Repository indicated that the association was stronger in -1123G > C compared to +1858C > T. In conclusion, the type 1 diabetes association with PTPN22 is confirmed, but it cannot be attributed solely to the +1858C > T variant. The promoter -1123G > C SNP is a more likely causative variant in PTPN22.

PTPN22 Trp620 Explains the Association of Chromosome 1p13 With Type 1 Diabetes and Shows a Statistical Interaction With HLA Class II Genotypes

“…For example, 73 kb telomeric of rs2476601/Arg620Trp, SNP rs6679677 is in perfect linkage disequilibrium with the PTPN22 functional candidate SNP and genetically and statistically, therefore, is as good a positional candidate as PTPN22 rs2476601/Arg620Trp. Our failure to obtain any evidence for allelic heterogeneity or haplotype effects in type 1 diabetes for this chromosome region suggests that for type 1 diabetes, previous studies (23,25,26) could have been false positives, especially because much smaller sample sizes were studied. We cannot comment on the validity of additional variants in rheumatoid arthritis and Graves' disease (22,24,28), except that any result should be replicated in additional datasets.…”

“…They identified a rare nsSNP K750N, which generates a premature stop codon, and presented some evidence of association with type 1 diabetes (P ϭ 0.026, minor allele frequency [MAF] ϭ 0.006). An Asian population study (25) did not detect the rs2476601/Arg620Trp variant in 1,690 Japanese or 180 Korean subjects but found a promoter SNP Ϫ1123G/C (rs2488457) to be associated with type 1 diabetes (P ϭ 0.0105; odds ratio (25). Furthermore, a Norwegian rheumatoid arthritis study of 861 case subjects and 559 control subjects (26) found they could not distinguish between Ϫ1123G/C (rs2488457) and rs2476601/Trp 620 because of linkage disequilibrium.…”

Type 1 diabetes in Japan

“…Furthermore, Lyp is among the most powerful inhibitors of T cell activation, a task accomplished by dephosphorylation of such molecules. However, we found that this locus was monomorphic in the Japanese population, and that the association was stronger in the promoter SNP than in R620W SNP even in multiplex families of white European origin [67]. These ethnic differences may be associated with susceptibility to or clinical outcomes of type 1 diabetes, and it will be necessary to investigate by biological analysis the mechanisms by which the variants produce disease susceptibility, as well as to investigate the origin of the variants by genetic dissection.…”

Association of STAT4 with Rheumatoid Arthritis in the Korean Population

“…However, the PTPN22 risk allele (R620W) is extremely rare in the Asian population and, so far, there is no evidence of association of PTPN22 with RA in non-White populations (8,9). In contrast, PADI4, SLC22A4, and FCRL3 have been associated with RA in the Japanese population and replicated in the other Asian groups (10)(11)(12), but have given weak or negative results in populations of European ancestry (13,14).…”