# Two DRB3 residues predictively associate with the progression to type 1 diabetes among DR3 carriers

## TL;DR

Two specific residues in the DRB3 gene influence the progression to type 1 diabetes in individuals carrying DRB1*03:01.

## Contribution

Identified two DRB3 residues with opposing effects on type 1 diabetes progression among DR3 carriers.

## Key findings

- Residues β11 and β26 in DRB3 are linked to delayed or accelerated progression to T1D.
- Motifs RY and LF at these residues show hazard ratios of 0.73 and 2.38, respectively.
- LF motif carriers progress faster to T1D compared to RY motif carriers.

## Abstract

HLA-DR genes are associated with the progression from stage 1 and stage 2 to onset of stage 3 type 1 diabetes (T1D), after accounting HLA-DQ genes with which they are in high linkage disequilibrium. Based on an integrated cohort of participants from 2 completed clinical trials, this investigation finds that, sharing a haplotype with the DRB1*03:01 (DR3) allele, DRB3*01:01:02 and *02:02:01 have respectively negative and positive associations with the progression. Furthermore, we uncovered 2 residues (β11, β26, participating in pockets 6 and 4, respectively) on the DRB3 molecule responsible for the progression among DR3 carriers; motif RY and LF respectively delay and promote the progression (hazard ratio [HR] = 0.73 and 2.38, P = 0.039 and 0.017, respectively). Two anchoring pockets 6 and 4 probably bind differential autoantigenic epitopes. We further investigated the progression association with the motifs RY and LF among carriers of DR3 and found that carriers of the motif LF have significantly faster progression than carriers of RY (HR = 1.48, P = 0.019 in unadjusted analysis; HR = 1.39, P = 0.047 in adjusted analysis), results of which provide an impetus to examine the possible role of specific DRB3-binding peptides in the progression to T1D.

Two residues in HLA-DRB3 gene have yin-yang associations with progression from stage 1 or 2 to stage 3 type 1 diabetes among carriers of DRB1*03:01.