ArticleEBioMedicine2021
The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes.
Article in EBioMedicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.
- Harnessing Machine Learning, a Subset of Artificial Intelligence, for Early Detection and Diagnosis of Type 1 Diabetes: A Systematic Review.International journal of molecular sciences · 2025Pooled it
- Genetic association and machine learning improve the prediction of type 1 diabetes risk.Nature genetics · 2026Article
- Evaluation of distinct and similar pathological features between diabetes and Alzheimer's disease.EXCLI journal · 2026Review
- Profiling associations of interactive ligand-receptors (HLA class I and KIR gene products) with the progression to type 1 diabetes among seroconverted participants.Diabetologia · 2025Article
- Preclinical Diagnosis of Type 1 Diabetes: Reality or Utopia.Biomedicines · 2025Review
- Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals.American journal of human genetics · 2025Article
- Research progress of SOCS in autoimmune diseases: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- Potential contribution of gut microbiota in the development of autoantibodies in T1D children carrying HLA-DRB1/DQB1 risk alleles: an experimental and in silico analysis.Immunogenetics · 2024Article
- Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes.Journal of internal medicine · 2023Review
- Association between alleles, haplotypes, and amino acid variations in HLA class II genes and type 1 diabetes in Kuwaiti children.Frontiers in immunology · 2023Article
- Important denominator between autoimmune comorbidities: a review of class II HLA, autoimmune disease, and the gut.Frontiers in immunology · 2023Review
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Authors and funding
18 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated.
methodsWe used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions.
findingsThree amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The "KAG" motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10 INTERPRETATIONS: DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65.
fundingNational Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.
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