Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study

Qu, Hui‐Qi; Tessier, M-C; Tj, Hudson; Polychronakos, Constantin

doi:10.1136/jmg.2004.026971

Cited by 62 publications

(37 citation statements)

References 19 publications

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“…25 Similar to the above-summarized murine model, an increased germinal center formation is observed in autoimmune models of pSS, SLE, and T1D. 26,27 As previously shown by others, 11,[28][29][30][31][32][33] our results disclosed that T allele is a risk factor for T1D (OR ¼ 1.83), although this difference was in the threshold of significance (P ¼ 0.06).…”

Section: Resultssupporting

confidence: 81%

PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases

Anaya

et al. 2005

Genes Immun

111

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Section: Resultssupporting

confidence: 81%

PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases

Anaya

et al. 2005

Genes Immun

111

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“…The analysis of the heterogeneity of the effect of PTPN22 on type 1 diabetes susceptibility corroborated previous observations that the PTPN22 1858T allele is associated with type 1 diabetes [10][11][12][14][15][16]. However, unlike in other studies, in both the case-control and the family series we observed that boys carrying the T allele were at higher risk of disease than girls.…”

Section: Discussionsupporting

confidence: 46%

“…The recent finding of association between the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) and type 1 diabetes has been reproduced in several white populations [10][11][12][13][14][15][16][17]. In addition, this variant appears to be a common predisposing factor for other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, Hashimoto thyroiditis and autoimmune Addison's disease [11,14,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes

et al. 2006

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Aims/hypothesis: We analysed the contribution of the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) to the emergence of beta-cellspecific humoral autoimmunity and progression to type 1 diabetes in man. We also explored the heterogeneity in the disease-predisposing effect of this polymorphism in relation to known disease loci, sex and age at disease onset. Subjects and methods: A population-derived Finnish birth cohort with increased disease susceptibility conferred by HLA-DQB1 was monitored for the appearance of islet cell autoantibodies, and individuals found to be positive were tested for autoantibodies against insulin (IAA), glutamic acid decarboxylase and islet antigen-2 (n=574; mean follow-up time 4.9 years). Gene interaction effects on disease susceptibility were analysed in case-control and family series (546 patients, 538 controls, 245 nuclear families). All subjects were typed for HLA DR-DQ, insulin gene (INS), CTLA4 and PTPN22 C1858T polymorphisms. Results: The PTPN22 1858TT genotype was associated with the appearance of IAA (adjusted hazard ratio=4.6, 95% CI 2.4-9.0; p=0.000013). PTPN22, INS and HLA-DRB1 had an additive effect on the emergence of IAA. The 1858TT and CT genotypes conferred an increased risk of developing additional autoantibodies or clinical disease (hazard ratio=4.1, 95% CI 1.5-11.6; and 1.6, 95% CI 1.1-2.4, respectively; p=0.003). The strong effect of PTPN22 on disease susceptibility (p=2.1×10 −8

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“…typing by the WTCCC GWA study, rs2476601/Arg620Trp was in perfect linkage disequilibrium (r 2 ϭ 1) with rs6679677, an intergenic SNP between the genes PHTF1 and RSBN1, in the 3,000 British control subjects; this near-perfect linkage disequilibrium has been reported by others (12,17). We genotyped rs6679677 and rs2476601/ Arg620Trp in the full case-control collection, with 7,500 case subjects and 7,200 control subjects.…”

Section: Ptpn22 In Type 1 Diabetesmentioning

confidence: 99%

“…With the exceptions of the MHC (2), cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-ICOS (6), IL2RA (8), and INS (4), which have been subjected to further resequencing and genotyping to try to narrow down candidates for the causal variant(s), the other type 1 diabetes loci have not yet been studied in any great detail (6,11,13). For PTPN22, there has been extensive focus on the single nsSNP rs2476601/Arg620Trp (7,(15)(16)(17)(18). Functional studies suggest that the Trp 620 allele has gain-offunction, immunosuppressive effects compared with the more common allele Arg 620 (19 -21).…”

mentioning

confidence: 99%

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

et al. 2008

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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.

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Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study

Cited by 62 publications

References 19 publications

PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases

PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases

Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes

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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