Journal article
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
eLife, v 12, 89068
02 Feb 2026
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- 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
- Creators
- Ozkan Aydemir - University of Massachusetts Chan Medical SchoolJeffrey A. Bailey - Brown UniversityDaniel Agardh - Lund UniversityAke Lernmark - Lund UniversityJanelle A. Noble - University of California, San FranciscoAgnes Andersson Svard - Lund UniversityElizabeth P. Blankenhorn - Drexel UniversityHemang M. Parikh - University of South FloridaAnette-G Ziegler - Ludwig-Maximilians-Universität MünchenJorma Toppari - University of TurkuBeena Akolkar - National Institute of Diabetes and Digestive and Kidney DiseasesWilliam A. Hagopian - Pacific Northwest Diabetes Research InstituteMarian J. Rewers - University of Colorado HealthJohn P. Mordes - University of Massachusetts Chan Medical SchoolTEDDY Study Grp
- Publication Details
- eLife, v 12, 89068
- Publisher
- eLIFE SCIENCES PUBL LTD
- Number of pages
- 29
- Grant note
- National Institute of Environmental Health Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) Eunice Kennedy Shriver National Institute of Child Health and Human Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) U01 DK63861 / National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:001678250200001
- Other Identifier
- 991022162824304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biology