RESUMO
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.).
Assuntos
Dapsona/efeitos adversos , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Adulto , Dapsona/uso terapêutico , Quimioterapia Combinada , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/genética , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNARESUMO
Thirty-three active multibacillary patients from nine counties of Weifang Prefecture, Shandong Province, and 47 active cases from Menla County, Yunnan Province, People's Republic of China, were treated with 24 and 27 months of multidrug therapy (MDT), respectively, in 1983. Clinical assessments, smears, and histopathologic examinations were carried out independently by study teams from the Institutes of Dermatology of these two provinces. Reexaminations at 12-14 months and at termination of therapy showed marked improvement, and there was continued improvement at 12-18 and 33 months on follow up. Conversion of the bacterial index to negativity was 0/33, 5/47 for the patients from Shandong and Yunnan provinces, respectively, at the end of MDT and 2/33 at 12 months' and 17/47 at 18 months' follow up, which increased to 21/33 and 26/44 at 33 months' follow up. Regression of specific infiltration was about 21%-100% after 24-27 months of MDT; further regression to 95%-100% occurred at 33 months' follow up.