HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Author:

Pugliese Alberto12,Boulware David3,Yu Liping4,Babu Sunanda4,Steck Andrea K.4,Becker Dorothy5,Rodriguez Henry6,DiMeglio Linda7,Evans-Molina Carmella8,Harrison Leonard C.9,Schatz Desmond10,Palmer Jerry P.11,Greenbaum Carla12,Eisenbarth George S.4,Sosenko Jay M.113,

Affiliation:

1. Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL

2. Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL

3. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL

4. Division of Bioinformatics and Biostatistics, University of South Florida, Tampa, FL

5. Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO

6. Department of Pediatrics at the Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA

7. Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL

8. Department of Pediatric Endocrinology, Riley Hospital for Children at Indiana University Health, Indianapolis, IN

9. Department of Medicine, Indiana University School of Medicine and the Richard L. Roudebush VA Medical Center, Indianapolis, IN

10. Department of Medical Biology, The Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Parkville, Victoria, Australia

11. Department of Pediatrics, University of Florida, Gainesville, FL

12. VA Puget Sound Health Care System and University of Washington, Seattle, WA

13. Benaroya Research Institute, Seattle, WA

Abstract

The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D.

Funder

National Institutes of Health

JDRF

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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