Abstract

Objective: Specific alleles of non-HLA genes INS, CTLA-4 and PTPN22 have been associated with type 1 diabetes (T1D). We examined whether some of these alleles influence development of islet autoimmunity (IA) or progression from persistent IA to T1D in children with high-risk HLA-DR,DQ genotypes.

Research Design and Methods: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed 2449 young children carrying HLA-DR,DQ genotypes associated with T1D. Of those, 112 have developed islet autoimmunity (persistent autoantibodies to insulin, GAD65 and/or IA-2) and 47 of these have progressed to T1D. The influence of polymorphisms of INS(-23Hph1), CTLA-4(T17A) and PTPN22(R620W) on development of persistent IA and progression to T1D was evaluated by parametric models and by survival analyses.

Results: PTPN22(R620W) allele T was associated with development of persistent IA (HR=1.83, 95% CI=1.27−2.63) controlling for ethnicity, presence of HLA-DR3/4,DQB1*0302, and first-degree relative with T1D. Survival analyses showed a significantly (p=0.002) higher risk of persistent IA by age 10 years for the TT genotype (27.3%) compared to the CT or CC genotype (7.9% and 5.3%, respectively). Cumulative risk of persistent IA was slightly higher (p=0.02) for the INS(-23Hph1) AA (7.8%) genotype compared to AT or TT (4.2% and 6.4% risk by age 10, respectively).

Conclusions: While the HLA-DR3/4,DQB1*0302 genotype had a dramatic influence on both development of IA and progression to T1D, PTPN22(R620W) T allele significantly influences progression to persistent IA in the DAISY cohort.