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OBJECTIVE- Specific alleles of non-HLA genes INS, CTLA-4, and PTPN22 have been associated with type 1 diabetes. We examined whether some of these alleles influence development of islet autoimmunity or progression from persistent islet autoimmunity to type 1 diabetes in children with high-risk HLADR, DQ genotypes.
RESEARCH DESIGN AND METHODS- Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,449 young children carrying HLA-DR,DQ genotypes associated with type 1 diabetes. Of those, 112 have developed islet autoimmunity (persistent autoantibodies to insulin, GAD65, and/or 1A-2), and 47 of these have progressed to type 1 diabetes. The influence of polymorphisms of Z/VS(-23Hphl), CTLA-4ÇT 17A), and PTPN22(R620W) on development of persistent islet autoimmunity and progression to type 1 diabetes was evaluated by parametric models and by survival analyses.
RESULTS- PTPN22(R620W) allele T was associated with development of persistent islet autoimmunity (hazard ratio 1.83 [95% CI 1.27-2.63]) controlling for ethnicity, presence of HLADR3/4,DQB1*0302, and having a first-degree relative with type 1 diabetes. Survival analyses showed a significantly (P = 0.002) higher risk of persistent islet autoimmunity by age 10 years for the TT genotype (27.3%) than for the CT or CC genotype (7.9 and 5.3%, respectively). Cumulative risk of persistent islet autoimmunity was slightly higher (P = 0.02) for the INS(-23Uphl) AA genotype (7.8%) than for the AT or TT genotype (4.2 and 6.4% risk by age 10 years, respectively).
CONCLUSIONS- Whereas the r7LA-DR3/4,DQB 1*0302 genotype had a dramatic influence on both development of islet autoimmunity and progression to type 1 diabetes, the PTPN22(R620W) T allele significanüy influences progression to persistent islet autoimmunity in the DAISY cohort Diabetes 58:1028-1033, 2009
The INS (insulin), CTLA-4 (polymorphic cytotoxic T-lymphocyte-associated antigen), and PTPN22 (protein tyrosine phosphatase nonreceptor type 22) genes are some of the confirmed non-HLA genes associated with type 1 diabetes (1-4). The INS gene on chromosome lip 15 confers about 10% of the genetic susceptibility to type 1 diabetes; both a variable number of tandem repeats located ~0.5 kb upstream of INS (1) and other polymorphisms in tight linkage disequilibrium (LD) such as -23HphI and +1140A/C (5) have been implicated as etiological factors. All of the polymorphisms lie outside coding sequences, suggesting that diabetes susceptibility derives from modulation of INS transcription (6).
The lymphoid-specific phosphatase (LYP),...