Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden

HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (alpha a1, alpha 44, alpha 157, alpha 196) and (beta 9, beta 30, beta 57, beta 70, beta 135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, DCAA-YSARD (OR=2.10, p=1.96*10(-20)), DQAA-YYARD (OR=3.34, 2.69*10(-72)) and DQDA-YYARD (OR=3.71, 1.53*10(-6)) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (alpha 44, beta 9, beta 30, beta 57 and beta 70), one was the N-terminal of the alpha chain (alpha a1), one in the CD4-binding region (beta 135), one in the putative cognate TCR-induced alpha beta homodimerization process (alpha 157), and one in the intra-membrane domain of the alpha chain (alpha 196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.

Automated summary

Using deep learning of DQ residue sequences, critical residues and motifs associated with T1D were uncovered on HLA-DQ molecules, including susceptibility and resistance associations. These residues, located on alpha and beta chains, play significant roles in the risk and protection against T1D.