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

¹Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

Objective: The disease association of the common 1858C>T Arg620Trp (rs2476601) nonsynonymous single nucleotide polymorphism (SNP) of protein tyrosine phosphatase; non-receptor 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 cateogory.

Research design and Methods: We resequenced PTPN22, and used these and other data to provide over 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 cases and 2,400 controls.

Results: Owing to linkage disequilibrium we were unable to distinguish between rs2476601/Trp⁶²⁰ (P = 2.11 x10^–87) and rs6679677 (P = 3.21 x10^–87), an intergenic SNP between the genes PHTF1and RSBN1. 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 rs2476601/Trp⁶²⁰ has a higher relative risk in type 1 diabetes cases 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/Trp⁶²⁰ remains the best candidate for the sole causal variant 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, therefore, we now have a convincing example of a non-multiplicative, gene-gene interaction involving a non-HLA gene in type 1 diabetes.

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