A1 Refereed original research article in a scientific journal
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
Authors: Aydemir, Ozkan; Bailey, Jeffrey A.; Agardh, Daniel; Lernmark, Ake; Noble, Janelle A.; Andersson Svard, Agnes; Blankenhorn, Elizabeth P.; Parikh, Hemang M.; Ziegler, Anette-G; Toppari, Jorma; Akolkar, Beena; Hagopian, William A.; Rewers, Marian J.; Mordes, John P.; TEDDY Study Group
Publisher: eLife Sciences Publications
Publication year: 2026
Journal: eLife
Article number: RP89068
Volume: 12
eISSN: 2050-084X
DOI: https://doi.org/10.7554/eLife.89068
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.7554/eLife.89068
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/515498823
Self-archived copy's licence: other license
Self-archived copy's version: Publisher`s PDF
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): both diseases are positively associated with the HLA-DR3 haplotype (DRB1*03:01-DQA1*05:01-DQB1*02:01). Studies of two different populations have recently documented that T1D susceptibility in HLA-DR3 homozygous individuals is stratified by a haplotype consisting of three single nucleotide polymorphisms (‘tri-SNP’) in intron 1 of the HLA-DRA gene. In this study, we use a large cohort from the longitudinal ‘The Environmental Determinants of Diabetes in the Young’ (TEDDY) study to further refine the tri-SNP association with T1D and with autoantibody-defined T1D endotypes. We found that the tri-SNP association is primarily in subjects whose first-appearing T1D autoantibody is to insulin. In addition, we discovered that the tri-SNP is also associated with CD, and that the particular tri-SNP haplotype (‘101’) that is negatively associated with T1D risk is positively associated with risk for CD. The opposite effect of the tri-SNP haplotype on two DR3-associated diseases can enhance and refine current models of disease prediction based on genetic risk. Finally, we investigated possible functional differences between the individuals carrying high and low-risk tri-SNP haplotypes and found that differences in complement system genes C4A and C4B may underlie the observed divergence in disease risk.
Downloadable publication This is an electronic reprint of the original article. |  |
Funding information in the publication:
Full details for the TEDDY Study Group can be found in Appendix 1. The TEDDY Study is funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and JDRF. This work is supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR002535). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
