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.