Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

Abstract

7Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins 8 play an essential role in the adaptive immune response for the presentation of self and non-self 9 peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug 10 induced agranulocytosis (severe lower white blood cell count) in patients with B*27:05, B*38:02 and 11 DRB1*08:03 alleles in different populations: Taiwanese, Vietnamese, Han Chinese and Caucasian. 12In this study, informatics methods were used to investigate if any sequence or structural similarities 13 exist between the two associated HLA-B alleles, compared with a set of "control" alleles assumed 14 not be associated, which could help explain the molecular basis of the adverse drug reaction. We 15 demonstrated using MHC Motif Viewer and MHCcluster that the two alleles do not have a 16propensity to bind similar peptides, and thus at a gross level the structure of the antigen 17 presentation region of the two alleles are not similar. We also performed multiple sequence 18 alignment to identify polymorphisms shared by the risk but not by the control alleles and molecular 19 docking to compare the predicted binding positions of the drug-allele combinations. 20 2 Two residues, Cys67 and Thr80, were identified from the multiple sequence alignments to be unique 21 to these risk alleles alone. The molecular docking showed the poses of the risk alleles to favour the 22 F-pocket of the peptide binding groove, close to the Thr80 residue, with the control alleles generally 23 favouring a different pocket. The data are thus suggestive that Thr80 may be a critical residue in 24 HLA-mediated anti-thyroid drug induced agranulocytosis, and thus can guide future research and 25 risk assessment. 26 that of abacavir with B*57:01. For this association, the crystal structure of the drug bound in 46 complex with the risk allele is available (8, 9). Illing et al. (8) and Ostrov et al. (9) have demonstrated 47