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

• Main Authors: Patompong Satapornpong, Jirawat Pratoomwun, Pawinee Rerknimitr, Jettanong Klaewsongkram, Nontaya Nakkam, Thanyada Rungrotmongkol, Parinya Konyoung, Niwat Saksit, Ajanee Mahakkanukrauh, Warayuwadee Amornpinyo, Usanee Khunarkornsiri, Therdpong Tempark, Kittipong Wantavornprasert, Pimonpan Jinda, Napatrupron Koomdee, Thawinee Jantararoungtong, Ticha Rerkpattanapipat, Chuang-Wei Wang, Dean Naisbitt, Wichittra Tassaneeyakul, Manasalak Ariyachaipanich, Thapana Roonghiranwat, Munir Pirmohamed, Wen-Hung Chung, Chonlaphat Sukasem
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-05-01
• Series: Frontiers in Immunology
• Subjects: dapsone-induced severe cutaneous adverse reactions; HLA class I and II alleles; HLA-B*13:01; cytochrome P450; Thais and Taiwaneses
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2021.661135/full

HLA-B*13:01 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 HLA 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. HLA class I and II alleles were genotyped using polymerase chain reaction-sequence specific oligonucleotides (PCR-SSOs). CYP2C9, CYP2C19, and CYP3A4 genotypes were determined by the TaqMan real-time PCR assay. We performed computational analyses of dapsone and DDS-NHOH interacting with HLA-B*13:01 and HLA-B*13:02 alleles by the molecular docking approach. Among all the HLA alleles, only HLA-B*13:01 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, HLA-B*13:01 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 HLA-B*13:01 allele and change the antigen-recognition site. However, there was no significant association between genetic polymorphism of cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) and dapsone-induced SCARs (SJS-TEN and DRESS). The results of this study support the specific genotyping of the HLA-B*13:01 allele to avoid dapsone-induced SCARs including SJS-TEN and DRESS before initiating dapsone therapy in the Asian population.