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.