HLA-B13 :01 Is a Predictive Marker of Dapsone-Induced Severe Cutaneous Adverse Reactions in Thai Patients

• Published in: Frontiers in immunology Vol. 12; p. 661135
• Main Authors: Satapornpong, Patompong, Pratoomwun, Jirawat, Rerknimitr, Pawinee, Klaewsongkram, Jettanong, Nakkam, Nontaya, Rungrotmongkol, Thanyada, Konyoung, Parinya, Saksit, Niwat, Mahakkanukrauh, Ajanee, Amornpinyo, Warayuwadee, Khunarkornsiri, Usanee, Tempark, Therdpong, Wantavornprasert, Kittipong, Jinda, Pimonpan, Koomdee, Napatrupron, Jantararoungtong, Thawinee, Rerkpattanapipat, Ticha, Wang, Chuang-Wei, Naisbitt, Dean, Tassaneeyakul, Wichittra, Ariyachaipanich, Manasalak, Roonghiranwat, Thapana, Pirmohamed, Munir, Chung, Wen-Hung, Sukasem, Chonlaphat
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04.05.2021
• Subjects: Adolescent; Adult; Aged; Alleles; Asian People - statistics & numerical data; Child; Child, Preschool; Cytochrome P-450 Enzyme System - genetics; cytochrome P450; Dapsone - adverse effects; dapsone-induced severe cutaneous adverse reactions; Female; Genetic Association Studies; Genetic Markers; Genotype; HLA class I and II alleles; HLA-B Antigens - classification; HLA-B Antigens - genetics; HLA-B13:01; Humans; Immunology; Male; Middle Aged; Molecular Docking Simulation; Polymorphism, Genetic; Prospective Studies; Skin - drug effects; Skin - pathology; Thais and Taiwaneses; Young Adult; HLA-B13:01; HLA class I and II alleles; Thais and Taiwaneses; cytochrome P450; dapsone-induced severe cutaneous adverse reactions
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.661135

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.