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47-ORdoi="10.1016/j.humimm.2013.08.058" aid="9232.47":IDENTIFICATION OF CLASS I AND CLASS II HLA EPITOPES IN TYPE 1 DIABETES

Human Immunology
DOI: 10.1016/j.humimm.2013.08.058
  • Medicine


Aim Disease susceptibility for type 1 diabetes (T1D) is strongly associated with the inheritance of specific HLA alleles. However, weak HLA associations may not be detected because many alleles are relatively rare and disparate alleles that have similar peptide-binding sites (shared epitopes) are not included. Methods We developed an R-based Epitope Analysis Program that can detect every possible epitope of 1-4 amino acids in the peptide-binding groove. The amino acids did not have to be contiguous. The number of individuals carrying at least one copy of the epitope was compared with the number of people not carrying the epitope. Results Two class I epitopes were most associated with T1D susceptibility: C67 in the HLA-B locus (p=1.7 x 10−6, OR=1.93) and IYH95,113,184 in the HLA-C locus (p=9.2 x 10−5, OR=1.84). Stronger associations were found with class II, including DRB1 H13 (p=4.2 x 10−57) and K71 (p=6.0 x 10−36, OR=3.59), DQA1 S26 (p=1.0 x 10−80, OR=7.15) and DQB1 A57 (p=1.3 x 10−87, OR=12.1). DRB1 R13 (p=3.9 x 10−34, OR=0.15), DRB1 A71 (p=3.5 x 10−36, OR=0.11), DQA1 Y80 (p=2.3 x 10−51, OR=0.22) and DQB1 D57 (p=7.1 x 10−97, OR=0.11) were strongly associated with resistance. A dominant resistance phenotype was seen for people bearing a protective HLA epitope, even in the presence of a susceptibility epitope. In addition, early disease onset was associated with significantly greater numbers of susceptibility epitopes and significantly fewer resistance epitopes (p&< 0.0001) [Fig. 1]. Conclusions Identifying HLA epitopes associated with T1D may lead to a better understanding of genetic susceptibility and help predict peptides that trigger autoimmunity.

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