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This version published online on February 7, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1695
A more recent version of this article appeared on May 1, 2006
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*Diabetes Type 1

Submitted on July 29, 2005
Accepted on February 1, 2006

Specific HLA DQ Influence on Expression of Anti-Islet Autoantibodies and Progression to Type 1 Diabetes

Maria J. Redondo, Sunanda Babu, Adina Zeidler, Tihamer Orban, Liping Yu, Carla Greenbaum, Jerry P. Palmer, David Cuthbertson, George S. Eisenbarth*, Jeffrey P. Krischer, Desmond Schatz, and and the DPT-1 Study Group reference 2

Department of Endocrinology. University Clinic of Navarra. Pamplona, Spain.; Barbara Davis Center for Childhood Diabetes. University of Colorado Health Sciences Center. Denver, CO.; Division of Endocrinology and Diabetes. LAC-University of Southern California Medical Center. Los Angeles, CA. Section of Immunology and Immunogenetics. Joslin Diabetes Center. Boston, MA. Diabetes Clinical Research. Benaroya Research Institute. Seattle, WA.; Department of Veterans Affairs Puget Sound, University of Washington. Seattle, WA.; Department of Pediatrics. University of South Florida, Tampa, FL.; Diabetes Center. University of Florida. Gainesville, FL

* To whom correspondence should be addressed. E-mail: george.eisenbarth{at}uchsc.edu.

Context: HLA DQ haplotypes have the strongest genetic association with type 1 diabetes (T1DM) risk.

Objective: To analyze whether HLA DQ alleles influence the development of anti-islet autoantibodies, the progression to T1DM among autoantibody-positive relatives, or both.

Design: The Diabetes Prevention Trial-1 (DPT-1) screened over 90,000 nondiabetic relatives of patients for cytoplasmic islet-cell autoantibody (ICA) expression between 1994 and 2002.

Setting: General community.

Participants: DPT-1 found 2,817 ICA-positive relatives who were tested for biochemical autoantibodies (GAD65A, ICA512A and mIAA) and HLA-DQ haplotypes, and 2,796 of them were followed for progression to diabetes for up to eight years (median of 3.6 yr).

Main Outcome Measure: Progression to T1DM.

Results: High-risk DQ haplotypes and genotypes were associated with a higher percentage of relatives expressing multiple biochemical autoantibodies, and higher T1DM risk (e.g. respectively, 59% and 36% at 5 yr for carriers of the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype). The number of autoantibodies expressed significantly increased T1DM risk and, across different DQ genotypes, autoantibody positivity directly correlated with diabetes risk. However, multivariate analyses indicated that the influence of most genotypes on T1DM risk was not independent from autoantibody expression, with the possible exception of DQA1*0102-DQB1*0602. Specific genotypic combinations conferred 5-year diabetes risks significantly lower (e.g. 7%-DQA1*0201-DQB1*0201/DQA1*0501-DQB1*0201, and 14%-DQA1*0301-DQB1*0301/DQA1*0501-DQB1*0201) than when those haplotypes were found in other combinations.

Conclusion: HLA DQ alleles determine autoantibody expression, which is correlated with diabetes progression. Among autoantibody-positive relatives, most HLA DQ genotypes did not further influence T1DM risk.






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