PTPN22 Trp620 Explains the Association of Chromosome 1p13 With Type 1 Diabetes and Shows a Statistical Interaction With HLA Class II Genotypes

Abstract

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/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. 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/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). 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 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.

Comparative Genetics: Synergizing Human and NOD Mouse Studies for Identifying Genetic Causation of Type 1 Diabetes

“…The results identified SNPs within two T1D-associated genes, PTPN22 and CTLA4, that alter the predicted disease risk of various HLA haplotypes. The interaction between PTPN22 and HLA class II genotypes confirms earlier work showing that the effect of a susceptibility allele at PTPN22 is greater in low-risk compared to high-risk HLA class II genotypes [86][87][88].…”

Association of PTPN22 gene polymorphism with type 1 diabetes mellitus in Chinese children and adolescents

“…Various recent publications have reported a relationship between PTPN22 and T1DM (Bottini et al, 2004;Kahles et al, 2005;Zheng and She, 2005;Steck et al, 2006;Nielsen et al, 2007;Smyth et al, 2004Smyth et al, , 2008Petrone et al, 2008;Saccucci et al, 2008;Dultz et al, 2009). Bottini et al (2004) were the first to report an association between the PTPN22 polymorphism and T1DM.…”

Genetic and Epigenetic Factors in Etiology of Diabetes Mellitus Type 1

“…21 Compared with PTPN22, there is no evidence for a statistical interaction with HLA class II genotypes for INS locus variants, further supporting the hypothesis that rs2476601/R620W is the most likely causal variant for T1D. 22 The latest advances in personalized medical genomics that are translated to the clinic are aimed at comprehensive sequencing of the disease genome, exome, epigenome, and transcriptomes. Next-generation sequencing technology has contributed to the precise mapping and quantification of chromatin features, DNA modifications, and several specific steps in the cascade of information from transcription to translation.…”