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. 2025 Mar;68(3):588-601.
doi: 10.1007/s00125-024-06338-7. Epub 2024 Dec 13.

Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes

Maria J Redondo  1 , David Cuthbertson  2 , Andrea K Steck  3 , Kevan C Herold  4 , Richard Oram  5 , Mark Atkinson  6 , Todd M Brusko  6 , Hemang M Parikh  2 , Jeffrey P Krischer  2 , Suna Onengut-Gumuscu  7 , Stephen S Rich  7 , Jay M Sosenko  8 ; Type 1 Diabetes TrialNet Study Group
Affiliations

Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes

Maria J Redondo et al. Diabetologia. 2025 Mar.

Abstract

Aims/hypothesis: Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.

Methods: We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant.

Results: IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, p<0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, p<0.001).

Conclusions/interpretation: Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.

Keywords: Autoantibodies; Diagnosis; Endotype; Genetics; Genotype; HLA; Heterogeneity; Immunologic; Phenotype; Precision medicine; Preclinical; Prediction; Screening; TrialNet; Type 1 diabetes.

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Conflict of interest statement

Acknowledgements: We are grateful to the TrialNet participants and their families. We thank Amanda L. Posgai, PhD (University of Florida Diabetes Institute, Gainesville, FL, USA) for her assistance in editing the manuscript. Data availability: The datasets generated and analysed during the current study are available from the Type 1 Diabetes TrialNet Coordinating Center on reasonable request. Funding: The Type 1 Diabetes TrialNet Study Group is a clinical trials network that is currently funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (through the cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993 and UC4 DK117009) and by the JDRF. The contents of this article are solely the responsibility of the authors, and do not necessarily represent the official views of the NIH or the JDRF. MJR is supported by NIH/NIDDK grants R01 DK124395 and R01 DK121843. Authors’ relationships and activities: MJR is a member of the Editorial Board of Diabetologia. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: MJR contributed to the study design, as well as data analysis and interpretation, and wrote the first draft of the manuscript. DC conducted data analysis and edited the manuscript. HMP contributed to data acquisition and analysis. AKS, KCH, RO, MA, TMB, HMP, JPK, SO-G and SSR contributed to data interpretation. JMS contributed to study design, data analysis, and interpretation and writing. All authors revised and edited the manuscript, and approved the final version to be published. MJR, DC, AKS, KCH, MA, TMB, HMP and JPK were members of the Type 1 Diabetes TrialNet Study Group at the time of the study. MJR and JMS are the guarantors of this article and take full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.

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