Effects of non-HLA gene polymorphisms on development of islet autoimmunity and type 1 diabetes in a population with high-risk HLA-DR,DQ genotypes.
We assessed the effects of non-HLA gene polymorphisms on the risk of islet autoimmunity (IA) and progression to type 1 diabetes in the Diabetes Autoimmunity Study in the Young. A total of 1,743 non-Hispanic, white children were included: 861 first-degree relatives and 882 general population children identified as having high-risk HLA-DR/DQ genotypes for type 1 diabetes. Of those, 109 developed IA and 61 progressed to diabetes. Study participants were genotyped for 20 non-HLA polymorphisms, previously confirmed as type 1 diabetes susceptibility loci. PTPN22 and UBASH3A predicted both IA and diabetes in regression models controlling for family history of type 1 diabetes and presence of HLA-DR3/4-DQB1*0302 genotype. In addition, PTPN2 predicted IA whereas INS predicted type 1 diabetes. The final multivariate regression models for both IA and type 1 diabetes included PTPN22, UBASH3A, and INS, in addition to family history of type 1 diabetes and HLA-DR3/4. In general population children, the most frequent combinations including these five significant predictors conferred hazard ratio of up to 13 for IA and >40 for type 1 diabetes. Non-HLA susceptibility alleles may help estimate risk for development of type 1 diabetes in the general population. These findings require replication in different populations.
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA. andrea.steck@ucdenver.edu
Andrea K
AK
Steck
Randall
R
Wong
Brandie
B
Wagner
Kelly
K
Johnson
Edwin
E
Liu
Jihane
J
Romanos
Cisca
C
Wijmenga
Jill M
JM
Norris
George S
GS
Eisenbarth
Marian J
MJ
Rewers
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; C423262:UBASH3A protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22