Pruning HLA alleles and drugs associated with ADRs
The gene/variant–drug relationship data were downloaded from the Pharmacogenomics Knowledge Base (PharmGKB) (accessed on January 25, 2019).12 Out of the 911 genes/variants and 797 drugs in the PharmGKB database, only 6 drugs and 7 HLA alleles with a high level of evidence were included in this study. Vancomycin and carbamazepine and their related HLA alleles HLA-A*32:01 and HLA-B*15:11, respectively, were also included after our expert panel discussion; however, they were not updated in the PharmGKB database. The detailed inclusion criteria are described in the Supplementary Materials. The following seven drugs were included: abacavir, allopurinol, carbamazepine, oxcarbazepine, dapsone, methazolamide, and vancomycin (Figure 1) . We focused on eight clinically significant HLA variants, namely, HLA-B*57:01, HLA-B*58:01, HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*13:01, HLA-B*59:01, and HLA-A*32:01, for the previously pruned drugs. As described in the Supplementary Materials, owing to the difference in the levels of representation of the HLA alleles, the HLA alleles were converted from the PharmGKB format to a 4-digit level (Supplementary Table 1). Table I presents the list of drugs, HLA alleles, and related ADRs included in this study. The level of evidence of the relationship in Table 1 was verified from PharmGKB, and the references were based on the PharmaGKB database or experts’ review.