Singapore scientists lead in the discovery of gene responsible for fatal drug allergy

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SCIENTIFIC PRESS RELEASE Embargoed until: 23 rd October 2013, 1700hrs, Massachusetts, USA 24 th October 2013, 0500hrs, Singapore Singapore scientists lead in the discovery of gene responsible for

1 SCIENTIFIC PRESS RELEASE Embargoed until: 23 rd October 2013, 1700hrs, Massachusetts, USA 24 th October 2013, 0500hrs, Singapore Singapore scientists lead in the discovery of gene responsible for fatal drug allergy 23 rd October 2013 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 (ADR 1 ) 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 23 rd 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 1 Harmful, unintended reactions to medicines that occur at doses normally used for treatment are called adverse drug reactions (ADRs)

2 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 allele 2. 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 sevenfold. 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 multidrug 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 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.

3 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. Notes to the Editor: Research publication The research findings described in the press release was published in the 23 rd October 2013 advanced online issue of New England Journal of Medicine under the title HLA-B*13:01 and Dapsone-Induced Hypersensitivity Syndrome. Authors: Fu-Ren Zhang, M.D., Ph.D., Hong Liu, M.D., Astrid Irwanto, B.Sc., Xi-An Fu, M.D., Yi Li, Ph.D., Gong-Qi Yu, B.S., Yong-Xiang Yu, B.S., Ming-Fei Chen, M.D., Hui-Qi Low, M.Sc., Jing-Hui Li, M.D., Fang-Fang Bao, M.D., Jia-Nee Foo, Ph.D., Jin-Xin Bei, Ph.D., Xiao-Ming Jia, M.D., M.Eng., Jian Liu, B.S., Herty Liany, M.Sc., Na Wang, B.S., Gui-Ye Niu, B.S., Zhen-Zhen Wang, M.D., Ben-Qing Shi, B.S., Hong-Qing Tian, M.D., Hua-Xu Liu, M.D., Ph.D., Shan-Shan Ma, B.S., Yan Zhou, B.S., Jia-Bao You, B.S., Qing Yang, M.D., Ph.D., Chuan Wang, M.D., Tong-Sheng Chu, M.D., Dian- Chang Liu, M.D., Xiu-Lu Yu, M.D., Yong-Hu Sun, M.D., Yong Ning, M.D., Zhong-He Wei, M.D., Sheng-Li Chen, M.D., Ph.D., Xue-Chao Chen, B.S., Zhao-Xia Zhang, M.D., Ph.D., Yong-Xia Liu, M.D., Sara L. Pulit, B.A., Wen-Bin Wu, M.D., Zhong-Yi Zheng, M.D., Rong-De Yang, M.D., Heng Long, M.D., Zuo-Sheng Liu, M.D., Jing- Quan Wang, M.D., Ming Li, M.D., Lian-Hua Zhang, M.D., Hong Wang, M.D., La-Mei Wang, M.D., Peng Xiao, M.D., Jin-Lan Li, M.D., Zhi-Ming Huang, M.D., Jun-Xin Huang, M.D., Zhen Li, M.D., Jian Liu, M.D., Li Xiong, M.D., Jun Yang, M.D., Xiao- Dong Wang, M.D., De-Bao Yu, M.D., Xian-Mei Lu, M.D., Gui-Zhi Zhou, M.D., Liang- Bin Yan, Ph.D., Jian-Ping Shen, Ph.D., Guo-Cheng Zhang, M.D., Yi-Xin Zeng, M.D., Ph.D., Paul I.W. de Bakker, Ph.D., Shu-Min Chen, M.D., Ph.D., and Jian-Jun Liu, Ph.D.

4 Affiliations: Shangdong Provincial Institute of Dermatology and Venereology, Jinan (F.-R.Z., H. Liu, X.-A.F., G.-Q.Y., Y.-X.Y., M.-F.C., J.-H.L., F.-F.B., J. Liu, N.W., G.-Y.N., Z.-Z.W., B.-Q.S., H.-Q.T., H.-X.L., S.-S.M., Y.Z., J.-B.Y., Q.Y., C.W., T.-S.C., D.-C.L., X.-L.Y., Y.-H.S., S.-L.C., X.-C.C., Z.-X.Z., Y.-X.L., X.-M.L., G.-Z.Z., S.-M.C.); Sichuan Provincial Institute of Dermatology, Chengdu (Y.N.); Hunan Provincial Center for Disease Control and Prevention, Changsha (Z.-H.W.); Fujian Center for Disease Control and Prevention, Fuzhou (W.-B.W.); Honghe Institute of Dermatology, Honghe, Yunnan (Z.-Y.Z.); Wenshan Institute of Dermatology, Wenshan, Yunnan (R.-D.Y., H. Long); Hubei Provincial Center for Disease Control and Prevention, Wuhan (Z.-S.L.); Zhejiang Provincial Institute of Dermatology, Deqing (J.-Q.W.); Guangdong Provincial Center for Disease Control and Prevention (M.L.) and State Key Laboratory of Oncology in South China, and Sun Yat-sen University Cancer Center, Department of Experiment Research (Y.-X.Z.), Guangzhou; Jiangsu Provincial Center for Disease Control and Prevention, Nanjing (L.-H.Z.); Guangxi Provincial Institute of Dermatology, Nanning (H.W.); Jiangxi Institute of Parasitic Disease, Nanchang (L.-M.W.); Chongqing Center for Disease Control and Prevention, Chongqing (P.X.); Guizhou Provincial Center for Disease Control and Prevention, Guizhou (J.-L.L.); Shenzhen Baoshan Chronic Disease Control Center (Z.-M.H.), Shenzhen Chronic Disease Control Center (J.-X.H.), and Shenzhen Nanshan Center for Disease Control and Prevention (Z.L.), Shenzhen; Tropical Medicine Research Institute of Beijing Friendship Hospital (J. Liu), and Institute of Dermatology, Chinese Academy of Medical Sciences, and Peking Union Medical College (L.-B.Y., J.-P.S., G.-C.Z.), Beijing; Yunnan Provincial Center for Disease Control and Prevention, Kunming, Yunnan (L.X., J.Y.); and Jinan Institute of Dermatology, Jinan (X.-D.W., D.-B.Y.) all in China; Genome Institute of Singapore, Singapore (A.I., Y.L., H.-G.L., J.-N.F., J.-X.B., H. Liany, J.-J.L.); the Division of Health Sciences and Technology, Harvard Massachusetts Institute of Technology, Cambridge, MA (X.-M.J.); the Departments of Medical Genetics (S.L.P., P.I.W.B.) and Epidemiology (P.I.W.B.) and the Julius Center for Health Sciences and Primary Care (P.I.W.B.), University Medical Center Utrecht, Utrecht, the Netherlands; the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA (S.L.P., P.I.W.B.); and the Division of Genetics, Brigham and Women s Hospital, Harvard Medical School, Boston (P.I.W.B.). * Correspondence: Prof Liu Jianjun liuj3@gis.a-star.edu.sg; Tel: (65) Contact Winnie Lim Genome Institute of Singapore Office of Corporate Communications Tel: (65) limcp2@gis.a-star.edu.sg About the Genome Institute of Singapore (GIS) The Genome Institute of Singapore (GIS) is an institute of the Agency for Science,

5 Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine. The key research areas at the GIS include Human Genetics, Infectious Diseases, Cancer Therapeutics and Stratified Oncology, Stem Cell and Developmental Biology, Cancer Stem Cell Biology, Genomic Technologies, Computational and Systems Biology, and Translational Technologies. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact. About the Agency for Science, Technology and Research (A*STAR) The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy. In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore s manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry. A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR s research entities as well as a growing number of corporate laboratories.

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