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Diabetes. 2008 Jun;57(6):1730-7. doi: 10.2337/db07-1131. Epub 2008 Feb 27.

PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes.

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Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.



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.


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.


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).


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.

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