Do non-HLA genes influence development of persistent islet autoimmunity and type 1 diabetes in children with high-risk HLA-DR,DQ genotypes?
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 HLA-DR,DQ genotypes.


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 IA-2), and 47 of these have progressed to type 1 diabetes. The influence of polymorphisms of INS(-23Hph1), CTLA-4(T17A), 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 HLA-DR3/4,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(-23Hph1) 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 HLA-DR3/4,DQB1*0302 genotype had a dramatic influence on both development of islet autoimmunity and progression to type 1 diabetes, the PTPN22(R620W) T allele significantly influences progression to persistent islet autoimmunity in the DAISY cohort.
Steck
Andrea K
AK
Barbara Davis Center for Childhood Diabetes, University of Colorado-Denver, Aurora, Colorado, USA. andrea.steck@uchsc.edu
Zhang
Weiming
W
Bugawan
Teodorica L
TL
Barriga
Katherine J
KJ
Blair
Alan
A
Erlich
Henry A
HA
Eisenbarth
George S
GS
Norris
Jill M
JM
Rewers
Marian J
MJ
D015703:Antigens, CD / Q000235:genetics*; D001323:Autoantibodies / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D060908:CTLA-4 Antigen; D002648:Child; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000503:physiopathology; D008297:Male; D009679:Nuclear Family; D011110:Polymorphism, Genetic; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*
D015703:Antigens, CD; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007328:Insulin; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22