Genetic association stratified by HLA-DR3 and HLA-DR4 status reveals heterogeneity in pathways of progression to type 1 diabetes

@article{luckett2026genetic,
  title = {{Genetic association stratified by HLA-DR3 and HLA-DR4 status reveals heterogeneity in pathways of progression to type 1 diabetes}},
  author = {Amber M. Luckett and Carolyn McGrail and Kathryn Murrall and Emily N. Griffin and Robin N. Beaumont and Gareth Hawkes and William A. Hagopian and Stephen S. Rich and Michael N. Weedon and Sarah Richardson and Richard A. Oram and Kyle J. Gaulton},
  journal = {Diabetologia},
  year = {2026},
  month = aug,
  doi = {10.1007/s00125-026-06836-w},
  url = {https://doi.org/10.1007/s00125-026-06836-w},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - Genetic association stratified by HLA-DR3 and HLA-DR4 status reveals heterogeneity in pathways of progression to type 1 diabetes
AU  - Amber M. Luckett
AU  - Carolyn McGrail
AU  - Kathryn Murrall
AU  - Emily N. Griffin
AU  - Robin N. Beaumont
AU  - Gareth Hawkes
AU  - William A. Hagopian
AU  - Stephen S. Rich
AU  - Michael N. Weedon
AU  - Sarah Richardson
AU  - Richard A. Oram
AU  - Kyle J. Gaulton
PY  - 2026
DA  - 2026/08/31
JO  - Diabetologia
DO  - 10.1007/s00125-026-06836-w
UR  - https://doi.org/10.1007/s00125-026-06836-w
AB  - Aims/hypothesis: There are substantial differences in the clinical presentation of type 1 diabetes depending on the first-developing autoantibody, although the underlying mechanisms are poorly understood. The DR3-DQ2 (DR3) and DR4-DQ8 (DR4) haplotypes at the MHC locus associate with GADA and IAA as the first-developing autoantibodies, respectively, and can therefore be used as proxies for first autoantibody development in large cohort studies of type 1 diabetes cases and control individuals.  Methods: We performed the first genome-wide association study of type 1 diabetes stratified by DR3 and DR4 status using 9091 type 1 diabetes cases and 14,157 control individuals from multiple cohorts. We estimated heritability and genetic correlation between type 1 diabetes with DR3 and DR4 (DR3-T1D and DR4-T1D, respectively), and with other immune and glycaemic phenotypes. We assessed heterogeneity in effects on type 1 diabetes between DR3 and DR4 individuals at known type 1 diabetes loci. We determined enrichment of type 1 diabetes heritability in DR3 and DR4 among variants in cell-type-specific cis-regulatory elements (cREs) and biological pathways, and annotated risk variants in cREs.  Results: We observed only moderate genetic correlation between DR4-T1D and DR3-T1D (rg=0.6), which was lower compared with stratifications based on age of onset and sex, and distinct patterns of genetic correlations with other autoimmune diseases. Among type 1 diabetes-associated loci, the IL2 locus had significantly larger effect on type 1 diabetes in DR4 while several other loci (TAGAP, KLRG1) had more nominal heterogeneity. There was stronger enrichment of DR4-T1D-associated variants in T cell cREs and T cell-related pathways, while DR3-T1D-associated variants were specifically enriched in mast cell cREs and secretion-related pathways. We finally prioritised specific loci annotated in mast cells with stronger effects on type 1 diabetes in DR3 individuals.  Conclusions/interpretation: We performed the first GWAS of type 1 diabetes stratified by DR3 and DR4 status, which revealed heterogeneity in genetic risk and biological mechanisms dependent on high-risk HLA background.  Graphical Abstract:  Supplementary Information: The online version contains peer-reviewed but unedited supplementary material available at https://doi.org/10.1007/s00125-026-06836-w.
SN  - 0012-186X
SN  - 1432-0428
ER  -