Novembe 16, 2011 -- Scientists at the Infectious Diseases department of the Genome Institute of Singapore (GIS), an institute of the Agency for Science, Technology and Research (A*STAR), led a genome-wide association study (GWAS) on a world-wide collaboration on Kawasaki disease. The study, published in Nature Genetics on 13 November 2011, indicates that the gene FCGR2A is associated with an increased risk of contracting the disease.
The world-wide investigation, linking five separate consortia, was initiated by GIS, which was responsible for the study design and coordination, as well as the laboratory work and data analysis of samples collected by its research partners. The study examined the genetic profiles of 405 children with Kawasaki disease and contrasted them with 6,252 healthy controls, in Europe, USA and Australia. Genetic markers showing potential association with the disease were re-assessed and validated in a further 740 affected families, as well as a further 1,028 affected children and 1,512 healthy controls from Asian countries.
From the study, the scientists noted very strong evidence of increased risk of disease at a gene encoding a protein called FCGR2A. This protein is well known to Kawasaki disease doctors because it is a receptor for intravenous immunoglobulin (IVIG), which is used for the treatment of Kawasaki disease. Their observation highlights the importance of such receptors in the pathogenesis of this inflammatory disease, and thereby provides a biological basis for the use of IVIG for Kawasaki disease treatment. Until now, researchers were unclear as to how or why the infusion of IVIG worked in treating the disease.
Co-lead author of the paper, Senior Group Leader and Associate Director for Infectious Diseases at the GIS, Dr Martin Hibberd said, “The cause and events that lead to Kawasaki disease have been difficult mysteries, that are now starting to be revealed, but only because of world-wide efforts such as this.Now we have added a very significant jigsaw piece to the big picture, I hope we can start to impact on patients through the development of early diagnosis and new therapeutic approaches.”
Dr Khor Chiea Chuen, co-first author and Research Scientist at the GIS added, “I saw my first patient with Kawasaki disease as a fourth year medical student five years ago, and when asked by the child’s parents regarding the cause of the disease, I didn’t know much apart from the observation that Kawasaki disease could be triggered by an infectious episode. Now, we know more. We plan to extend this study to involve Singaporean patients in the near future.”
Kawasaki disease is an autoimmune disease in which patient’s blood vessels throughout the body become inflamed. It affects mostly children, causing prolonged fever of usually more than five days. It is unresponsive to antibiotics and anti-pyrectics, such as paracetomol and aspirin. A very visible rash develops, and the child is in obvious discomfort, but it cannot be relieved by traditional means. Furthermore, there are other conditions, such as scarlet fever and measles, which can mimic it, and thus delay its diagnosis. Early diagnosis is important, so that IVIG can be administered straightaway. If IVIG is delayed, there is a significant risk of irreversible heart damage.
The research findings described in the press release can be found in the 13 November 2011 advance online publication of Nature Genetics under the title “Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease”.
Chiea Chuen Khor1–3,29, Sonia Davila2,4,29, Willemijn B Breunis5,6,29, Yi-Ching Lee7, Chisato Shimizu8,9, Victoria J Wright10, Rae S M Yeung11–13, Dennis E K Tan4, Kar Seng Sim4, Jie Jin Wang14,15, Tien Yin Wong14,16,17, Junxiong Pang1,18, Paul Mitchell14, Rolando Cimaz19,20, Nagib Dahdah21, Yiu-Fai Cheung22, Guo-Ying Huang23, Wanling Yang22, In-Sook Park24, Jong-Keuk Lee18, Jer-Yuarn Wu7, Michael Levin10,30, Jane C Burns8,9,30, David Burgner25,26,30, Taco W Kuijpers5,6,30, Martin L Hibberd1,3,30, Hong Kong–Shanghai Kawasaki Disease Genetics Consortium28, Korean Kawasaki Disease Genetics Consortium28, Taiwan Kawasaki Disease Genetics Consortium28, International Kawasaki Disease Genetics Consortium28 & US Kawasaki Genetics Consortium28.
Hong Kong–Shanghai Kawasaki Disease Genetics Consortium: Yu-Lung Lau31, Jing Zhang31, Xiao-Jing Ma32, Fang Liu32 & Lin Wu32
Korean Kawasaki Disease Genetics Consortium: Jeong-Jin Yoo33, Soo-Jong Hong33, Kwi-Joo Kim33, Jae-Jung Kim34, Young-Mi Park34, Young Mi Hong35, Sejung Sohn35, Gi Young Jang36, Kee-Soo Ha36, Hyo-Kyoung Nam36, Jung-Hye Byeon36, Sin Weon Yun37, Myung Ki Han38, Kyung-Yil Lee39, Ja-Young Hwang39, Jung-Woo Rhim39, Min Seob Song40, Hyoung-Doo Lee41, Dong Soo Kim42 & Jae-Moo Lee43
Taiwan Kawasaki Disease Genetics Consortium: Jeng-Sheng Chang44, Fuu-Jen Tsai44, Chi-Di Liang45, Ming-Ren Chen46, Hsin Chi46, Nan-Chang Chiu46, Fu-Yuan Huang46, Luan-Yin Chang47, Li-Min Huang47, Ho-Chang Kuo45,48, Kao-Pin Huang45,48, Meng-Luen Lee49, Betau Hwang50, Yhu-Chering Huang51 & Pi-Chang Lee52??
International Kawasaki Disease Genetics Consortium: Miranda Odam25,53, Frank T Christiansen53, Campbell Witt54, Paul Goldwater55,56, Nigel Curtis24,57, Pamela Palasanthiran58, John Ziegler58, Michael Nissen59, Clare Nourse60, Irene M Kuipers61, Jaap J Ottenkamp61, Judy Geissler61, Maarten Biezeveld61, Carline Tacke61, Luc Filippini62, Paul Brogan63, Nigel Klein63, Vanita Shah63, Michael Dillon63, Robert Booy64, Delane Shingadia64, Anu Bose64, Thomas Mukasa64, Robert Tulloh65 & Colin Michie66
US Kawasaki Genetics Consortium: Jane W Newburger67, Annette L Baker67, Anne H Rowley68, Stanford T Shulman68, Wilbert Mason69, Masato Takahashi70, Marian E Melish71 & Adriana H Tremoulet72
Blue Mountains Eye Study: Ananth Viswanathan73, Elena Rochtchina74, John Attia75, Rodney Scott75, Elizabeth Holliday75 & Stephen Harrap76
1 Infectious Diseases, Genome Institute of Singapore, Singapore.
2 National University of Singapore–Genome Institute of Singapore Centre for Molecular Epidemiology??, Singapore.
3 Department of Epidemiology and Public Health, Faculty of Medicine, National University of Singapore, Singapore.
4 Human Genetics, Genome Institute of Singapore, Singapore.
5 Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children’s Hospital Academic Medical Center, Amsterdam, The Netherlands.
6 Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands.
7 Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan.
8 Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
9 Department of Pediatrics, Rady Children’s Hospital, San Diego, California, USA.
10 Department of Pediatrics, Imperial College London, London, UK.
11 Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
12 Department of Immunology, University of Toronto, The Hospital for Sick Children, Toronto, Canada.
13 Department of Medical Science, University of Toronto, The Hospital for Sick Children, Toronto, Canada.
14 Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia.
15 Centre for Vision Research, The University of Sydney, Sydney, New South Wales, Australia.
16 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
17 Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
18 Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, South Korea.
19 Rheumatology Unit, Anna Meyer Children’s Hospital, Florence, Italy.
20 Department of Pediatrics, University of Florence, Florence, Italy.
21 Division of Pediatric Cardiology, Sainte-Justine University Hospital Center, University of Montreal, Montreal, Quebec, Canada.
22 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong.
23 Pediatric Cardiovascular Center, Children’s Hospital, Fudan University, Shanghai, China.
24 Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
25 Murdoch Childrens Research Institute, The Royal Children’s Hospital, Parkville, Victoria, Australia.
26 School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
27 Department of Paediatrics, Faculty of Medicine, National University of Singapore, Singapore.
28 Complete list of authors and affiliations appear at the end of this paper.
29 These authors contributed equally to this work.
30 These authors jointly directed this work.
31 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong.
32 Pediatric Cardiovascular Center, Children’s Hospital, Fudan University, Shanghai, China
33 Department of Pediatrics, Asan Medical Center, Seoul, Korea.
34 Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
35 Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea.
36 Department of Pediatrics, Korea University Hospital, Seoul, Korea.
37 Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea.
38 Department of Pediatrics, University of Ulsan, Gangneung Asan Hospital, Gangneung, Korea.
39 Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary’s Hospital, Daejeon, Korea.
40 Department of Pediatrics, Inje University Paik Hospital, Busan, Korea.
41 Department of Pediatrics, Pusan National University Hospital, Busan, Korea.
42 Department of Pediatrics, Yonsei University College of Medicine, Severance Children’s Hospital, Seoul, Korea.
43 Seoul Clinical Laboratories, Seoul, Korea.
44 Department of Pediatrics, China Medical University and Hospital, Taichung, Taiwan.
45 Department of Pediatrics, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Kaohsiung, Taiwan.
46 Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
47 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
48 Department of Allergy and Immunology, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Kaohsiung, Taiwan.
49 Department of Pediatrics and Division of Pediatric Cardiology, Changhua Christian Hospital, Changhua, Taiwan.
50 Department of Pediatrics, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan.
51 Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.
52 Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
53 School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia.
54 Department of Clinical Immunology and Immunogenetics, PathWest Royal Perth Hospital, Perth, Western Australia, Australia.
55 SA Pathology, North Adelaide, South Australia, Australia.
56 School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
57 The University of Melbourne and Royal Children’s Hospital Melbourne, Parkville, Victoria, Australia.
58 Sydney Children’s Hospital, Randwick, New South Wales, Australia.
59 School of Medicine, Faculty of Health Sciences, University of Queensland, Brisbane, Queensland, Australia.
60 Mater Children’s Hospital, Faculty of Paediatrics, University of Queensland, Brisbane, Queensland, Australia.
61 Emma Children’s Hospital Academic Medical Center, Amsterdam, The Netherlands.
62 Juliana Children’s Hospital, The Hague, The Netherlands.
63 The Institute of Child Health, London, UK.
64 Royal London Hospital, London, UK.
65 Bristol Royal Hospital for Children, Bristol, UK.
66 Ealing Hospital, London, UK.
67 Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts, USA.
68 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Children’s Memorial Hospital, Chicago, Illinois, USA.
69 Department of Pediatrics, Children’s Hospital Los Angeles, California, USA.
70 Department of Cardiology, Los Angeles Children’s Hospital, Los Angeles, California, USA.
71 Department of Pediatrics, Kapliolani Children’s Hospital, Honolulu, Hawaii, USA.
72 University of California San Diego, La Jolla, California, USA.
73 University College London, London, UK
74 The University of Sydney, Sydney, New South Wales, Australia.
75 University of Newcastle, Newcastle, New South Wales, Australia.
76 University of Melbourne, Melbourne, Victoria, Australia.
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About the Genome Institute of Singapore
The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, 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 Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. 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. www.gis.a-star.edu.sg
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences and physical sciences and engineering research institutes, and six consortia & centres, located in Biopolis and Fusionopolis as well as their immediate vicinity.
A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, and with other local and international partners. www.a-star.edu.sg