HLA-DPB1*0402 protects against type 1A diabetes autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population.
OBJECTIVE
A major goal in genetic studies of type 1A diabetes is prediction of anti-islet autoimmunity and subsequent diabetes in the general population, as >85% of patients do not have a first-degree relative with type 1A diabetes. Given prior association studies, we hypothesized that the strongest candidates for enhancing diabetes risk among DR3-DQB1*0201/DR4-DQB1*0302 individuals would be alleles of DP and DRB1*04 subtypes and, in particular, the absence of reportedly protective alleles DPB1*0402 and/or DRB1*0403.


METHODS
We genotyped 457 DR3-DQB1*0201/DR4-DQB1*0302 Diabetes Autoimmunity Study of the Young (DAISY) children (358 general population and 99 siblings/offspring of type 1 diabetic patients) at the DPB1, DQB1, and DRB1 loci using linear arrays of immobilized sequence-specific oligonucleotides, with direct sequencing to differentiate DRB1*04 subtypes.


RESULTS
By survival curve analysis of DAISY children, the risk of persistently expressing anti-islet autoantibodies is approximately 55% for relatives (children with a parent or sibling with type 1 diabetes) in the absence of these two protective alleles vs. 0% (P = 0.02) with either protective allele, and the risk is 20 vs. 2% (P = 0.004) for general population children. Even when the population analyzed is limited to DR3-DQB1*0201/DR4-DQB1*0302 children with DRB1*0401 (the most common DRB1*04 subtype), DPB1*0402 influences development of anti-islet autoantibodies.


CONCLUSIONS
The ability to identify a major group of general population newborns with a 20% risk of anti-islet autoimmunity should enhance both studies of the environmental determinants of type 1A diabetes and the design of trials for the primary prevention of anti-islet autoimmunity.
Baschal
Erin E
EE
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, CO 80045-6511, USA.
Aly
Theresa A
TA
Babu
Sunanda R
SR
Fernando
Maria S
MS
Yu
Liping
L
Miao
Dongmei
D
Barriga
Katherine J
KJ
Norris
Jill M
JM
Noble
Janelle A
JA
Erlich
Henry A
HA
Rewers
Marian J
MJ
Eisenbarth
George S
GS
D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D005838:Genotype; D006681:HLA-D Antigens; D006682:HLA-DP Antigens / Q000276:immunology*; D059868:HLA-DP beta-Chains; D006683:HLA-DQ Antigens / Q000276:immunology*; D059866:HLA-DQ beta-Chains; D006650:Histocompatibility Testing; D006801:Humans; D009679:Nuclear Family; D018570:Risk Assessment; D013534:Survival
D006681:HLA-D Antigens; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen