Profiling associations of interactive ligand–receptors (HLA class I and KIR gene products) with the progression to type 1 diabetes among seroconverted participants
An erratum to this article was published (Diabetologia, Dec 2025 ↗)
Authors' conclusion
These results reveal that LRIs of KIR-HLA-I gene products, rather than individual genes, contribute to type 1 diabetes progression, and such interactions are likely to be stabilised by electrostatic and van der Waals forces. As the KIR-HLA-I interactions involve part of the C-terminus of the antigen-binding groove of HLA-I, but may be affected by the respective bound peptide, this suggests a new mechanism for type 1 diabetes pathogenesis.
Study context
- Population
- Seroconverted participants (stage 1 or 2 T1D) in the Diabetes Prevention Trial-Type 1 (DPT-1) and the Diabetes Prevention Trial (TN07)
- Participants
- 1,215 participants
- Comparison
- Carriers vs non-carriers of HLA-I–KIR ligand–receptor interactions
- Outcome
- T1D progression from stages 1 or 2 to stage 3
Methodological detailsnext-generation sequencing, Cox regression, homology modelling
- Next-generation sequencing
- Cox regression
- Homology modelling
Main finding
As reported in the abstract
Hazard ratio
0.36
P = 3.06 × 10-2
A*03:01-KIR2DS4 carriers
Hazard ratio
0.26
P = 7.76 × 10-3
B*07:02-KIR2DL3 carriers
- HLA-A ligands with corresponding receptors with modest associations with progression (p<0.05)
- 9
- HLA-B ligands with corresponding receptors with modest associations with progression (p<0.05)
- 14
Further findings
Structural properties of KIR-HLA-I complexes (homology modelling)
- Electrostatic and van der Waals interactions encoded in the protein sequences suggested to result in strong biophysical ligand-receptor interactions (LRIs), which could alter T1D progression
Original publication
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