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Polymorphisms in Intron 1 of HLA-DRA Differentially Associate with Type 1 Diabetes and Celiac Disease and Implicate Involvement of Complement System Genes C4A and C4B

  1. Özkan Aydemir author has email address
  2. Jeffrey A. Bailey
  3. Daniel Agardh
  4. Åke Lernmark
  5. Janelle A. Noble
  6. Agnes Andersson Svärd
  7. Elizabeth P. Blankenhorn
  8. Hemang Parikh
  9. Anette-G. Ziegler
  10. Jorma Toppari
  11. Beena Akolkar
  12. William A. Hagopian
  13. Marian J. Rewers
  14. John P. Mordes
  15. TEDDY Study Group
  1. University of Massachusetts Chan Medical School, Worcester, MA, USA
  2. Department of Pathology and Laboratory Medicine and Center for Computational Molecular Biology, Brown University, Providence, RI, USA
  3. Department of Clinical Sciences, Lund University CRC Skane University Hospital, Malmö, Sweden
  4. University of California San Francisco, San Francisco, CA, USA
  5. Drexel University College of Medicine, Philadelphia, PA, USA
  6. Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
  7. Institute of Diabetes Research, Helmholtz Zentrum München, Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V., Neuherberg, Germany
  8. Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, and Centre for Population Health Research, University of Turku, Turku, Finland
  9. Department of Pediatrics, Turku University Hospital, Turku, Finland
  10. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
  11. Pacific Northwest Research Institute, Seattle, WA, USA
  12. Department of Medicine, University of Washington, Seattle, WA, USA
  13. Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.

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Editors

  • Reviewing Editor
    Edward Janus
    University of Melbourne, Melbourne, Australia
  • Senior Editor
    Tadatsugu Taniguchi
    University of Tokyo, Tokyo, Japan

Reviewer #1 (Public Review):

Polymorphisms in genes in the human leukocyte antigen (HLA) class II region comprise the most important inherited risk factors for many autoimmune diseases including type 1 diabetes (T1D) and celiac disease (CD). The paper focuses on the novel triad ((SNPs): rs3135394, rs9268645, and rs3129877) finding quite interesting results. The paper suggests further studies at the molecular and structural level to increase our fundamental knowledge of the etiology of autoimmune deceases.

Reviewer #2 (Public Review):

In this manuscript, Aydemir et al. utilized the large TEDDY study and examined the effect of previously identified tri-SNP in the HLA-DRA gene on the risk of type 1 diabetes (T1D) and celiac disease (CD). They confirmed the protective effect of the tri-SNP haplotype "101" on T1D development. Meanwhile, the same haplotype appeared to be positively associated with risk for CD and the development of CD autoimmunity. The authors further explored the molecular effect of different tri-SNP haplotypes. They proposed that C4A and C4B might be the downstream target.

Overall, the study is rigorously conducted with proper statistical methods applied. The tri-SNP could be used as an additional risk factor when estimating T1D and celiac disease susceptibility in genetic screening. However, how this locus be incorporated into the current scheme of genetic screening is not discussed and is unlikely to be straightforward.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation