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

Hermann, Róbert; Lipponen, Kati; Kiviniemi, Minna; Kakko, Tanja; Veijola, Riitta; Simell, Olli; Knip, Mikael; Ilonen, Jorma

doi:10.1007/s00125-006-0225-4

Cited by 92 publications

(93 citation statements)

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“…We have provided evidence of statistical interaction between HLA class II genotypes and a non-MHC HLA susceptibility locus in agreement with two previous studies from Hermann et al (29) and Steck et al (30). This interaction, which is less than multiplicative, cannot be interpreted biologically (42), and all that we are able to conclude from it is that despite the relative risk of PTPN22 being higher in low-risk HLA genotypes, the combined risk of diabetes for individuals carrying high-risk HLA and PTPN22 genotypes is higher than that for those carrying low risk HLA genotypes and high-risk PTPN22 genotypes.…”

Section: Discussionsupporting

confidence: 92%

“…Hermann et al (29) observed that the effect of rs2476601/Trp 620 was more pronounced in subjects with non-DR4-DQ8/low-risk HLA genotypes (P ϭ 0.0004) from a dataset of 546 case subjects, 538 control subjects, and 245 nuclear families from Finland (mean age at diagnosis of case subjects 8.2 Ϯ 4.1 years). They also reported some evidence that boys carrying the rs2476601 Trp 620 allele were at higher risk of disease than girls (P ϭ 0.021; 29).…”

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confidence: 99%

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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

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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Section: Discussionsupporting

confidence: 92%

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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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“…Similar findings have been reported previously to extend to several autoimmune diseases (4,5) and on the appearance of insulin autoantibodies (IAA) in individuals positive for islet cell autoantibodies (ICAϩ) (23) and the risk of RF-positive rheumatoid arthritis (24). These observations support that the 1858T allele has a dose-dependant effect on the risk of several autoimmune diseases, including type 1 diabetes, consistent with the hypothesis that the underlying mechanisms may depend on a specific threshold (5).…”

Section: Discussionsupporting

confidence: 87%

PTPN22 R620W Functional Variant in Type 1 Diabetes and Autoimmunity Related Traits

et al. 2007

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The PTPN22 gene, encoding the lymphoid-specific protein tyrosine phosphatase, a negative regulator in the T-cell activation and development, has been associated with the susceptibility to several autoimmune diseases, including type 1 diabetes. Based on combined case-control and family-based association studies, we replicated the finding of an association of the PTPN22 C1858T (R620W) functional variant with type 1 diabetes, which was independent from the susceptibility status at the insulin gene and at HLA-DR (DR3/4 compared with others). The risk contributed by the 1858T allele was increased in patients with a family history of other autoimmune diseases, further supporting a general role for this variant on autoimmunity. In addition, we found evidence for an association of 1858T allele with the presence of GAD autoantibodies (GADA), which was restricted to patients with long disease duration (>10 years, P < 0.001). This may help define a subgroup of patients with long-term persistence of GADA. The risk conferred by 1858T allele on GAD positivity was additive, and our meta-analysis also supported an additive rather than dominant effect of this variant on type 1 diabetes, similar to previous reports on rheumatoid arthritis and systemic lupus erythematosus. Diabetes 56:522-526, 2007

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“…This may be due to the inclusion criteria used, resulting in a relatively homogeneous study population, but may also reflect the idea that factors contributing to the initiation of the disease process might be different from those driving the process towards overt disease. However, as previously shown (2,3,6,21,22), several of the factors associated with the initiation of b-cell autoimmunity do contribute to the phenomena associated with the progression rate, such as age at initial seroconversion, the pace of progression towards persistent multipositivity and autoantibody levels. The current study confirmed the prior observations that progression to T1D is related to young age at seroconversion, early progression to multipositivity, higher numbers of detectable autoantibodies and to higher levels of ICA, IAA and IA-2A (1, 2, 3).…”

Section: Discussionmentioning

confidence: 81%

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

Siljander

Hermann

Hekkala

et al. 2013

European Journal of Endocrinology

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Objective: Reduced early insulin response has been shown to predict type 1 diabetes (T1D) in firstdegree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced b-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies. Design and methods: Intravenous glucose tolerance tests (IVGTTs) were carried out in 218 children with HLA-DQB1-conferred disease susceptibility and advanced b-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed. Results: Children developing T1D were younger at seroconversion, progressed more rapidly to advanced b-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D. Conclusions: Young age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children with HLA-DQB1-conferred disease susceptibility and advanced b-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

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

Cited by 92 publications

References 50 publications

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

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

PTPN22 R620W Functional Variant in Type 1 Diabetes and Autoimmunity Related Traits

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

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