TY - JOUR KW - Adult KW - Dapsone KW - Drug Hypersensitivity KW - Drug Therapy, Combination KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - genotype KW - HLA-B Antigens KW - Humans KW - Leprostatic Agents KW - leprosy KW - Male KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sequence Analysis, DNA AU - Zhang F-R AU - Liu H AU - Irwanto A AU - Fu X-A AU - Li Y AU - Yu G-Q AU - Yu Y-X AU - Chen M-F AU - Low H-Q AU - Li J-H AU - Bao F-F AU - Foo J-N AU - Bei J-X AU - Jia X-M AU - Liu J AU - Liany H AU - Wang N AU - Niu G-Y AU - Wang Z-Z AU - Shi B-Q AU - Tian H-Q AU - Liu H-X AU - Ma S-S AU - Zhou Y AU - You J-B AU - Yang Q AU - Wang C AU - Chu T-S AU - Liu D-C AU - Yu X-L AU - Sun Y-H AU - Ning Y AU - Wei Z-H AU - Chen S-L AU - Chen X-C AU - Zhang Z-X AU - Liu Y-X AU - Pulit S L AU - Wu W-B AU - Zheng Z-Y AU - Yang R-D AU - Long H AU - Liu Z-S AU - Wang J-Q AU - Li M AU - Zhang L-H AU - Wang H AU - Wang L-M AU - Xiao P AU - Li J-L AU - Huang Z-M AU - Huang J-X AU - Li Z AU - Liu J AU - Xiong L AU - Yang J AU - Wang X-D AU - Yu D-B AU - Lu X-M AU - Zhou G-Z AU - Yan L-B AU - Shen J-P AU - Zhang G-C AU - Zeng Y-X AU - Bakker P I W AU - Chen S-M AU - Liu J-J AB -
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.).
BT - The New England journal of medicine C1 - http://www.ncbi.nlm.nih.gov/pubmed/24152261?dopt=Abstract CN - ZHANG 2013 DA - 2013 Oct 24 DO - 10.1056/NEJMoa1213096 IS - 17 J2 - N. Engl. J. Med. LA - eng N2 -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.).
PY - 2013 SP - 1620 EP - 8 T2 - The New England journal of medicine TI - HLA-B*13:01 and the dapsone hypersensitivity syndrome. VL - 369 SN - 1533-4406 ER -