HLA-B*13 :01 Is a Predictive Marker of Dapsone-Induced Severe Cutaneous Adverse Reactions in Thai Patients

<i>HLA-B*13:01</i> allele has been identified as the genetic determinant of dapsone hypersensitivity syndrome (DHS) among leprosy and non-leprosy patients in several studies. Dapsone hydroxylamine (DDS-NHOH), an active metabolite of dapsone, has been believed to be responsible for DHS. However, studies have not highlighted the importance of other genetic polymorphisms in dapsone-induced severe cutaneous adverse reactions (SCAR). We investigated the association of <i>HLA</i> alleles and cytochrome P450 (CYP) alleles with dapsone-induced SCAR in Thai non-leprosy patients. A prospective cohort study, 16 Thai patients of dapsone-induced SCARs (5 SJS-TEN and 11 DRESS) and 9 Taiwanese patients of dapsone-induced SCARs (2 SJS-TEN and 7 DRESS), 40 dapsone-tolerant controls, and 470 general Thai population were enrolled. <i>HLA</i> class I and II alleles were genotyped using polymerase chain reaction-sequence specific oligonucleotides (PCR-SSOs). <i>CYP2C9</i>, <i>CYP2C19</i>, and <i>CYP3A4</i> genotypes were determined by the TaqMan real-time PCR assay. We performed computational analyses of dapsone and DDS-NHOH interacting with <i>HLA-B*13:01</i> and <i>HLA-B*13:02</i> alleles by the molecular docking approach. Among all the <i>HLA</i> alleles, only <i>HLA-B*13:01</i> allele was found to be significantly associated with dapsone-induced SCARs (OR = 39.00, 95% CI = 7.67-198.21, p = 5.3447 × 10^-7), SJS-TEN (OR = 36.00, 95% CI = 3.19-405.89, p = 2.1657 × 10^-3), and DRESS (OR = 40.50, 95% CI = 6.38-257.03, p = 1.0784 × 10^-5) as compared to dapsone-tolerant controls. Also<i>, HLA-B*13:01</i> allele was strongly associated with dapsone-induced SCARs in Asians (OR = 36.00, 95% CI = 8.67-149.52, p = 2.8068 × 10^-7) and Taiwanese (OR = 31.50, 95% CI = 4.80-206.56, p = 2.5519 × 10^-3). Furthermore, dapsone and DDS-NHOH fit within the extra-deep sub pocket of the antigen-binding site of the <i>HLA-B*13:01</i> allele and change the antigen-recognition site. However, there was no significant association between genetic polymorphism of cytochrome P450 (<i>CYP2C9</i>, <i>CYP2C19</i>, and <i>CYP3A4</i>) and dapsone-induced SCARs (SJS-TEN and DRESS). The results of this study support the specific genotyping of the <i>HLA-B*13:01</i> allele to avoid dapsone-induced SCARs including SJS-TEN and DRESS before initiating dapsone therapy in the Asian population.