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(620), suggesting that it may not be the sole 
causal variant in the region and that the relative risk of rs2476601/Trp(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(620) (P = 2.11 x10(-87)) and rs6679677 (P = 3.21 x10(-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(620). We did 
not detect any interaction with age at diagnosis or sex. However, we found that 
rs2476601/Trp(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(-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(620) 
remains the best candidate in this chromosome region in European populations. 
The heterogeneity of rs2476601/Trp(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.