AUTHOR=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 

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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.661135

DOI=10.3389/fimmu.2021.661135

ISSN=1664-3224

ABSTRACT=<p><italic>HLA-B*13:01</italic> 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 <italic>HLA</italic> 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. <italic>HLA</italic> class I and II alleles were genotyped using polymerase chain reaction-sequence specific oligonucleotides (PCR-SSOs). <italic>CYP2C9</italic>, <italic>CYP2C19</italic>, and <italic>CYP3A4</italic> genotypes were determined by the TaqMan real-time PCR assay. We performed computational analyses of dapsone and DDS-NHOH interacting with <italic>HLA-B*13:01</italic> and <italic>HLA-B*13:02</italic> alleles by the molecular docking approach. Among all the <italic>HLA</italic> alleles, only <italic>HLA-B*13:01</italic> allele was found to be significantly associated with dapsone-induced SCARs (OR = 39.00, 95% CI = 7.67–198.21, p = 5.3447 × 10<sup>−7</sup>), SJS-TEN (OR = 36.00, 95% CI = 3.19–405.89, p = 2.1657 × 10<sup>−3</sup>), and DRESS (OR = 40.50, 95% CI = 6.38–257.03, p = 1.0784 × 10<sup>−5</sup>) as compared to dapsone-tolerant controls. Also<italic>, HLA-B*13:01</italic> allele was strongly associated with dapsone-induced SCARs in Asians (OR = 36.00, 95% CI = 8.67–149.52, p = 2.8068 × 10<sup>−7</sup>) and Taiwanese (OR = 31.50, 95% CI = 4.80–206.56, p = 2.5519 × 10<sup>−3</sup>). Furthermore, dapsone and DDS-NHOH fit within the extra-deep sub pocket of the antigen-binding site of the <italic>HLA-B*13:01</italic> allele and change the antigen-recognition site. However, there was no significant association between genetic polymorphism of cytochrome P450 (<italic>CYP2C9</italic>, <italic>CYP2C19</italic>, and <italic>CYP3A4</italic>) and dapsone-induced SCARs (SJS-TEN and DRESS). The results of this study support the specific genotyping of the <italic>HLA-B*13:01</italic> allele to avoid dapsone-induced SCARs including SJS-TEN and DRESS before initiating dapsone therapy in the Asian population.</p>