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Specific Human Leukocyte Antigen DQ Influence on Expression of Antiislet Autoantibodies and Progression to Type 1 Diabetes

Department of Endocrinology (M.J.R.), University Clinic of Navarra, 31008 Pamplona, Spain; Barbara Davis Center for Childhood Diabetes (S.B., L.Y., G.S.E.), University of Colorado Health Sciences Center, Denver, Colorado 80045-6511; Division of Endocrinology and Diabetes (A.Z.), Los Angeles County-University of Southern California Medical Center, Los Angeles, California 90033; Section of Immunology and Immunogenetics (T.O.), Joslin Diabetes Center, Boston, Massachusetts 02215; Diabetes Clinical Research (C.G.), Benaroya Research Institute, Seattle, Washington 98101; Department of Veterans Affairs Puget Sound (J.P.P.), University of Washington, Seattle, Washington 98108; Department of Pediatrics (D.C., J.P.K.), University of South Florida, Tampa, Florida 33612; and Diabetes Center (D.S.), University of Florida, Gainesville, Florida 32611

Address all correspondence and requests for reprints to: George S. Eisenbarth, M.D., Ph.D., Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 1775 North Ursula Street, P.O. Box 6511, Aurora, Colorado 80045-6511. E-mail: george.eisenbarth{at}uchsc.edu.

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

Objective: The objective of the study was to analyze whether HLA DQ alleles influence the development of antiislet autoantibodies, the progression to T1DM among autoantibody-positive relatives, or both.

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

Setting: The study was conducted in the general community.

Participants: The Diabetes Prevention Trial-1 found 2817 ICA-positive relatives who were tested for biochemical autoantibodies (GAD65, ICA512, and insulin) and HLA-DQ haplotypes, and 2796 of them were followed up for progression to diabetes for up to 8 yr (median, 3.6 yr).

Main Outcome Measure: Progression to T1DM was measured.

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-yr 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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