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

  1. Erin E. Baschal1,
  2. Theresa A. Aly1,
  3. Sunanda R. Babu1,
  4. Maria S. Fernando1,
  5. Liping Yu1,
  6. Dongmei Miao1,
  7. Katherine J. Barriga1,
  8. Jill M. Norris2,
  9. Janelle A. Noble3,
  10. Henry A. Erlich4,
  11. Marian J. Rewers1 and
  12. George S. Eisenbarth1
  1. 1Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, Colorado
  2. 2Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
  3. 3Children's Hospital Oakland Research Institute, Oakland, California
  4. 4Roche Molecular Systems, Alameda, California
  1. Address correspondence and reprint requests to George S. Eisenbarth, MD, PhD, Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Mail Stop B140, P.O. Box 6511, Aurora, CO 80045-6511. E-mail: george.eisenbarth{at}uchsc.edu

Abstract

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.

RESEARCH DESIGN AND 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 ∼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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 18 May 2007. DOI: 10.2337/db07-0029.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 13, 2007.
    • Received January 9, 2007.
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  1. Published online before print May 18, 2007, doi: 10.2337/db07-0029 Diabetes September 2007 vol. 56 no. 9 2405-2409
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