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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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/Trp620, suggesting that it may not be the sole causal variant in the region and that the relative risk of rs2476601/Trp620 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/Trp620 (P = 2.11 ×10−87) and rs6679677 (P = 3.21 ×10−87), 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/Trp620. We did not detect any interaction with age at diagnosis or sex. However, we found that rs2476601/Trp620 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 × 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/Trp620 remains the best candidate in this chromosome region in European populations. The heterogeneity of rs2476601/Trp620 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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