HLA-B*13:01 and the dapsone hypersensitivity syndrome.

BACKGROUND: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome. METHODS: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls. RESULTS: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans. CONCLUSIONS: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).

HLA linked with leprosy in southern China: HLA-linked resistance alleles to leprosy.

According to the World Health Organization recommended multidrug therapy (WHO/MDT), we have carried out this study to investigate the presence of HLA-linked susceptibility or resistance to leprosy in a southern Chinese population. Sixty-nine leprosy patients and 112 healthy controls participated in the study. HLA-DR2 subtypes, HLA-B and MHC Class I chain-related A (MICA) alleles were typed at the DNA level using the polymerase chain reaction-single strand conformation polymorphism method. The frequencies of HLA-DR2-DRB1 alleles did not show any significant differences between the patient and the control groups, suggesting that the disease susceptibility was not associated with the DR2 subtypes in this southern Chinese population. On the other hand, in the multibacillary (MB) patients significantly decreased allele frequencies of HLA-B46 (0.040 in MB patients vs 0.129 in controls) and MICA-A5 (0.200 vs 0.380) were observed compared with the healthy controls. The calculated relative risk (RR) for B46 was 0.28; for MICA-A5, 0.52. In addition, on haplotype analysis the frequency of the HLA-B46/MICA-A5 haplotype was significantly decreased in the MB patients compared to controls (0.060 vs 0.233, RR = 0.22, p < 0.01). These results suggest that an HLA-linked disease-resistant gene to MB leprosy in southern China is in strong linkage disequilibrium with the HLA-B46/MICA-A5 haplotype. In other words, the resistant gene may be located near the HLA-B/MICA region and not in the HLA-DR locus.