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HLA-DPB1*0402 Protects Against Type 1A Diabetic Autoimmunity in the Highest Risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY Population

Erin E. Baschal^*, Theresa A. Aly^*, Sunanda R. Babu^*, Maria S. Fernando^*, Liping Yu^*, Dongmei Miao^*, Katherine J. Barriga^*, Jill M. Norris, Janelle A. Noble, Henry A. Erlich, Marian J. Rewers^*, and George S. Eisenbarth^*

*Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, Colorado 80045 USA;
Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262 USA;
Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA;
Roche Molecular Systems, Alameda, CA 94710, USA

Correspondence: George.Eisenbarth{at}UCHSC.edu

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 more than 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 amongst 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.

Research Design and Methods:We genotyped 457 DR3-DQB1*0201/DR4-DQB1*0302 DAISY children (358 general population and 99 siblings/offspring of type 1 diabetes 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 children in the DAISY study, 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 versus 0% (p=0.02) with either protective allele, and the risk is 20% versus 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.

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