Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes.
OBJECTIVE
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-cell-specific 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.


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 x 10(-8)) was more pronounced in males (p = 0.021) and in subjects with non-DR4-DQ8/low-risk HLA genotypes (p = 0.0004).


CONCLUSIONS
In the pathogenesis of type 1 diabetes the underlying mechanism of the PTPN22 C1858T polymorphism appears to involve regulation of insulin-specific autoimmunity. Importantly, it strongly affects progression from prediabetes to clinical disease.
Hermann
R
R
JDRF Centre for Prevention of Type 1 Diabetes in Finland, Turku, Finland. robert.hermann@utu.fi
Lipponen
K
K
Kiviniemi
M
M
Kakko
T
T
Veijola
R
R
Simell
O
O
Knip
M
M
Ilonen
J
J
D000293:Adolescent; D019943:Amino Acid Substitution; D001120:Arginine; D001323:Autoantibodies / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007330:Insulin Antibodies / Q000097:blood*; D008297:Male; D008403:Mass Screening; D009679:Nuclear Family; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012727:Sex Characteristics; D014364:Tryptophan
D001323:Autoantibodies; D006683:HLA-DQ Antigens; D007330:Insulin Antibodies; D014364:Tryptophan; D001120:Arginine; C516765:PTPN22 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases; D005968:Glutamate Decarboxylase