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OBJECTIVE--The disease association of the common 1858C>T Arg620Trp (rs2476601) nonsynonymous single nucleotide polymorphism (SNP) of protein tyrosine phosphatase; nonreceptor type 22 (PTPN22) on chromosome 1p13 has been confirmed in type 1 diabetes and also in other autoimmune diseases, including rheumatoid arthritis and Graves' disease. Some studies have reported additional associated SNPs independent of rs2476601/Trp[sup 620], suggesting that it may not be the sole causal variant in the region and that the relative risk of rs2476601/Trp[sup 620] is greater in lower risk by HLA class II genotypes than in the highest risk class II risk category. RESEARCH DESIGN AND METHODS--We resequenced PTPN22 and used these and other data to provide >150 SNPs to evaluate the association of the PTPN22 gene and its flanking chromosome region with type 1 diabetes in a minimum of 2,000 case subjects and 2,400 control subjects. RESULTS--Due to linkage disequilibrium, we were unable to distinguish between rs2476601/Trp[sup 620] (P = 2.11 x 10[sup -87]) and rs6679677 (P = 3.21 x 10[sup -87]), an intergenic SNP between the genes putative homeodomain transcription factor 1 and round spermatid basic protein 1. None of the previously reported disease-associated SNPs proved to be independent of rs2476601/ Trp[sup 620]. We did not detect any interaction with age at diagnosis or sex. However, we found that rs2476601/Trp[sup 620] has a higher relative risk in type 1 diabetic case subjects carrying lower risk HLA class II genotypes than in those carrying higher risk ones (P = 1.36 x 10[sup -4] in a test of interaction). CONCLUSIONS--In our datasets, there was no evidence for allelic heterogeneity at the PTPN22 locus in type 1 diabetes, indicating that the SNP rs2476601/Trp[sup 620] remains the best candidate in this chromosome region in European populations. The heterogeneity of rs2476601/Trp[sup 620] disease risk by HLA class II genotype is consistent with previous studies, and the joint effect of the two loci is still greater in the high-risk group. Diabetes 57: 1730-1737, 2008 [ABSTRACT FROM AUTHOR]

The strong familial clustering of autoimmune type 1 diabetes in families remains only partially explained. The six confirmed genes or chromosome regions with convincing statistical support (P < 10[sup-9]) in large, and multiple, populations, namely the major histocompatibility complex (MHC), the insulin gene (INS), CTLA4, PTPN22, IL2RA/CD25, and the interferon-induced helicase 1 gene region (IFIH1/MDA5), can explain only about 50% of familial aggregation. Nonetheless, their identification has provided many insights into the biology and pathways of type I diabetes, often closely mirroring findings in the spontaneous animal models of the disease. Recent expansions in sample collections, including the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory (JDRF/WT DIL) British T1D case sample (n = 8,000), and advances in affordable, genome-wide, high throughput single nucleotide polymorphism (SNP) genotyping technologies (Affymetrix), has allowed an association analysis of 500,000 SNPs across the genome in 2,000 type 1 diabetes cases and 3,000 controls as part of the Wellcome Trust Case-Control Consortium (WTCCC). Attesting to the quality of the SNP map, positive results were obtained for all six susceptibility loci reported previously. However, follow-up genotyping studies of 14 other chromosome regions showing P < 10[sup-5] in the WTCCC scan in over 6,000 cases and 6,000 controls, and in approximately 2,000 families, supported in a convincing way (P < l0[sup-15] and odds ratios approximately 1.2) three new regions associated with type 1 diabetes in both the family and case-control samples, on chromosomes 16p13 (rs12708716), 12q13 (rs11171739) and 12q24 (rs17696736). The chromosome 12 loci map to regions of linkage disequilibrium containing many genes, although the chromosome 16p13 locus maps to a region containing two functional candidate genes, MHC2TA, which regulates HLA class II expression and the suppressor of cytokine signalling gene, SOCS1, and the third gene of unknown function, KIAA0350. These results illustrate how powerful the genome-wide association approach is in the systematic characterisation of the genetic basis of type 1 diabetes. [ABSTRACT FROM AUTHOR]