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A team of researchers led by Prof Liu Jianjun from A*STAR's Genome Institute of Singapore (GIS) has discovered that the presence of a gene allele known as HLA-B*13:01 could cause a severe adverse drug reaction (ADR1) to dapsone, which could be fatal. The important discovery will lead to the development of HLA-B*13:01-based diagnostic tests, which will identify high-risk individuals of this potentially life-threatening condition, and help improve the safety of dapsone therapy. The finding was reported in the 23rd October 2013 advanced online issue of the prestigious scientific journal, New England Journal of Medicine.
Dapsone (diamino-diphenyl sulfone) is a drug used in the treatment of various forms of infectious and inflammatory diseases and is commonly prescribed for the treatment of leprosy. Up to 3.6% of individuals treated with dapsone develop a severe adverse drug reaction known as dapsone hypersensitivity syndrome (DHS) and between 11% and 13% die as a result. This is alarming as no test is currently available to predict the risk of DHS in patients.
Prof Liu, Senior Group Leader of Human Genetics and Deputy Director of Research Programmes at the GIS, and his colleagues performed a genome-wide association study on 76 DHS patients and 1,304 controls, and discovered that the presence of a particular HLA-B molecule (called HLA-B*13:01) increased the risk of DHS.
Individuals carrying a single copy of HLA-B*13:01 run 34 times the risk of being hit by DHS as compared to those who do not carry this allele2. The scientists further found that the risk is magnified 100 times for those who carry two copies of HLA-B*13:01.
This study also showed that the allele HLA-B*13:01 has a sensitivity and specificity of above 85% in predicting the risk of DHS. Additionally, the implementation of HLA-B*13:01-based diagnostic testing reduces the risk of DHS by an impressive seven-fold.
Prof Liu said, "This is an excellent testimony that human genetic studies are a powerful tool to discover novel biomarkers and biological insight into disease development as well as adverse drug reactions. Genetic studies of ADR can help to improve the safety of drug treatment. However, ADRs are very much understudied, particularly in the Asian population. More such studies of ADRs are needed."
Co-lead author Prof Furen Zhang, Director, Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Science, China, said, "Dapsone used to be widely prescribed for treating infectious and inflammatory diseases in China and other countries. However, prescription of the drug has been dramatically declining recently because of its life-threatening side effects. Today, dapsone is mainly used for the treatment of leprosy as one component of the multi-drug therapy regimen. The discovery of HLA-B1301 allele as a risk factor for DHS will enable us to develop a clinical test kit for HLA-B1301 allele and thus, DHS risk prediction. If a patient is found to carry the risk allele, he or she will be prescribed alternative drugs rather than dapsone, thus preventing DHS. By the wide distribution of the test kit for HLA-B1301 allele, we can not only reduce the incidence of DHS among leprosy patients, but also promote the prescription of dapsone worldwide by improving its safety."
Dr Benjamin Seet, Executive Director at the Biomedical Research Council, A*STAR, added, "Pharmacogenomics ushers in a revolution in the way medicine will be practised in the not-too-distant future. We will see a progressive shift from treatment protocols developed from population-based observations and studies, to precision treatments determined by each individual's genetic make-up. This will allow for more targeted interventions and enhanced patient safety."
Dr Michael Hayden, Director of the Translational Laboratory in Genetic Medicine (TLGM) and Distinguished Professor, Department of Medicine, National University of Singapore said, "Dapsone is a particularly important drug for treatment of infectious diseases. The dapsone hypersensitivity syndrome is a major adverse event with significant morbidity and mortality. The identification of a generic risk marker that predicts dapsone hypersensitivity syndrome is a major advancement with significant clinical relevance."
Executive Director of the GIS, Prof Huck Hui Ng said, "ADRs have increasingly come to the forefront of concern because they are among the leading causes of fatality in many countries. Drugs that are meant to treat patients can sometimes kill them. Prof Liu and his team's discovery of the HLA-B*13:01 allele which greatly increases the risk of ADR in patients being treated with dapsone will indeed help save lives."
1 Harmful, unintended reactions to medicines that occur at doses normally used for treatment are called adverse drug reactions (ADRs)
2 An allele is one of a number of alternative forms of the same gene or same group of genes. Different alleles can result in different observable characteristics, such as different eye colour, blood type or skin colour.
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, and J.-J. Liu
N Engl J Med 2013; 369:1620-1628October 24, 2013DOI: 10.1056/NEJMoa1213096
Genome Institute of Singapore
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