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

Abstract

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.).

• Authors: F-R Zhang, H Liu, A Irwanto, X-A Fu, Y Li, G-Q Yu, Y-X Yu, M-F Chen, H-Q Low, J-H Li, F-F Bao, J-N Foo, J-X Bei, X-M Jia, J Liu, H Liany, N Wang, G-Y Niu, Z-Z Wang, B-Q Shi, H-Q Tian, H-X Liu, S-S Ma, Y Zhou, J-B You, Q Yang, C Wang, T-S Chu, D-C Liu, X-L Yu, Y-H Sun, Y Ning, Z-H Wei, S-L Chen, X-C Chen, Z-X Zhang, Y-X Liu, S L Pulit, W-B Wu, Z-Y Zheng, R-D Yang, H Long, Z-S Liu, J-Q Wang, M Li, L-H Zhang, H Wang, L-M Wang, P Xiao, J-L Li, Z-M Huang, J-X Huang, Z Li, J Liu, L Xiong, J Yang, X-D Wang, D-B Yu, X-M Lu, G-Z Zhou, L-B Yan, J-P Shen, G-C Zhang, Y-X Zeng, P I W de Bakker, S-M Chen, J-J Liu
• Journal: The New England journal of medicine (N Engl J Med) Vol. 369 Issue 17 Pg. 1620-8 (Oct 24 2013) ISSN: 1533-4406 [Electronic] United States
• PMID: 24152261 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-B Antigens
• Leprostatic Agents
• Dapsone

Topics

• Adult
• Dapsone (adverse effects, therapeutic use)
• Drug Hypersensitivity (genetics)
• Drug Therapy, Combination
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• HLA-B Antigens (genetics)
• Humans
• Leprostatic Agents (adverse effects, therapeutic use)
• Leprosy (drug therapy, genetics)
• Male
• Polymorphism, Single Nucleotide
• Risk Factors
• Sequence Analysis, DNA