Combined Effect of Glutamine at Position 70 of HLA-DRB1 and Alaline at Position 57 of HLA-DQB1 in Type 1 Diabetes: An Epitope Analysis

Abstract

study Abstract The contribution of specific HLA Class II alleles in type 1 diabetes is determined by polymorphic amino acid epitopes that direct antigen binding therefore, along with conventional allele frequency analysis, epitope analysis can provide important insights into disease susceptibility. Within our highly genetically heterogeneous patient cohort we identified a subgroup that did not carry the DRB1*03:01-DQA1*05:01-DQB1*02:01 and DRB1*04:xx-DQA1*03:01-DQB1*03:02 susceptibility epitopes DRB1 Q 70 , DQB1 L 26 and resistance epitopes DRB1 D 70 , R 70 and DQB1 Y 47 . Prevalence of susceptibility epitopes was higher in patients and was not exclusively a result of linkage disequilibrium. Epitopes DRB1 Q 70 , DQB1 L 26 and A 57 and a 10 amino acid epitope of DQA1 were the most significant in discriminating risk alleles. An extended haplotype containing these epitopes was carried by 92% of our patient cohort. Sharing of susceptibility epitopes could also explain the absence of risk haplotypes in patients. Finally, many significant epitopes were non-pocket residues suggesting that critical immune functions exist spanning further from the binding pockets.