Amino acid variants of HLA-DRB1 confer susceptibility to dapsone hypersensitivity syndrome in addition to HLA-B*13:01.

Dapsone hypersensitivity syndrome is a rare yet severe adverse drug reaction caused by dapsone, a principal drug in the multidrug therapy for leprosy. HLA-B*13:01 has been identified to be a strong risk factor of dapsone hypersensitivity syndrome, however its low positive predictive value indicated that additional genetic variants may involve in the disease development. To discover contributing genetic variants within HLA loci in addition to HLA-B*13:01, we performed a high coverage next-generation sequencing based HLA typing analysis in 103 dapsone-hypersensitive and 857 dapsone-tolerant HLA-B*13:01 positive leprosy patients in Chinese population. Five amino acid variants in high linkage disequilibrium of HLA-DRB1 were significantly associated with dapsone hypersensitivity syndrome (position 133, 142, -17, 11, 13). DRB1*16:02 and DRB1*15:01 tagged by these risk-conferring amino acid residues were associated at nominal significance level. This study identifies five amino acid variants within HLA-DRB1 that are in high linkage disequilibrium and significantly associated with dapsone hypersensitivity syndrome in Chinese population.