Study opens new possibilities for scientists to create genetic tests and future treatments for Exfoliation Syndrome
Singapore — An international research collaboration led by Singaporean researchers have led to the discovery of a mutated gene that renders people highly susceptible to a severe eye disorder called Exfoliation Syndrome (XFS). The study involved 8,400 patients from 17 countries and was reported in the prestigious scientific journal, Nature Genetics.
The scientists found that Singaporean Chinese with the mutation are 40 to 56 percent more likely to develop XFS some time in their lives compared to Singaporean Chinese without the mutation. They also noted that Singaporean Indians with the mutation are between 19 to 25 percent more likely to develop XFS some time in their lives compared against Singaporean Indians without the mutation. This figure is in stark contrast to the global average of 16 to 25 per cent of similar individuals likely to develop XFS. The study is led by researchers from A*STAR’s Genome Institute of Singapore (GIS) and the Singapore Eye Research Institute (SERI).
XFS usually develops in people above the age of 60 years old and is characterised by the body’s inability to remove abnormal protein deposits from inside the eye. The accumulation of these protein deposits clogs the eye’s drainage mechanism that results in a build-up of fluid and pressure in the eye in a condition called Glaucoma. If left untreated, a person with glaucoma can become permanently blind.
The gene believed to be responsible for XFS is called CACNA1A. The scientists found that CACNA1A affects the body’s calcium transport channels, which are important for many vital biological functions. Those who carry the CACNA1A gene have faulty calcium transport channels that hinder normal bodily functions, such as the eye’s ability to efficiently remove abnormal protein deposits.
A*STAR’s Dr Khor Chiea Chuen from GIS said, “Glaucoma is one of the most common eye diseases in Singapore and around the world. With this knowledge, we can now concentrate our efforts to develop therapeutic solutions to address and normalise the calcium signalling function in order to reduce the risk of XFS and the development of glaucoma.”
SERI Executive Director and Senior Consultant and Head of Glaucoma Service, Singapore National Eye Centre, Prof Aung Tin said, “This is an exciting discovery as the pathway we have found could be a target for new therapies and medications to prevent or treat this type of glaucoma.”
“On a personal level,” added Prof Aung, “the project was extremely stimulating and interesting as we were working with more than 90 collaborating sites from 17 different countries in Asia, Europe, Australia, Africa, North America and South America. It was a huge honour for us in Singapore to be coordinating and leading this global study of such scale and impact.”
Prof Robert Ritch, Shelley and Steven Einhorn Distinguished Chair, Professor of Ophthalmology and Surgeon Director and Chief (Glaucoma Services) at The New York Eye and Ear Infirmary said, “This new gene may not only explain some of the manifestations of Exfoliation Syndrome, but may also help us explain why associated systemic diseases occur in conjunction with it. This discovery opens doors to further elucidation, understanding, and perhaps new treatments for Exfoliation Syndrome.” Prof Ritch is also the founder, medical director and chairman of the Scientific Advisory Board at The Glaucoma Foundation.
“This is a very important study showing association of a novel DNA variant with disease risk in populations throughout the world,” added Janey L. Wiggs, who holds the post as the Paul Austin Chandler Associate Professor of Ophthalmology at the Harvard Medical School. Prof Wiggs jointly supervised the project.
“Exfoliation Syndrome is a debilitating disorder affecting many people in the world. The study is highly relevant to local as well as some foreign populations. The next step after this study is to capture the value from this new knowledge and turn it into health outcomes, such as to develop a genetic test to screen for XFS and new treatments for individuals carrying the CACNA1A gene,” said Prof Ng Huck Hui, Executive Director, GIS.
Notes to Editor:
The research findings described in the media release can be found in the Nature Genetics journal, under the title, “A common variant mapping to CACNA1A is associated with susceptibility to Exfoliation syndrome” by Tin Aung*1,2,3, Mineo Ozaki*4,34, Takanori Mizoguchi*5, R Rand Allingham6*, Zheng Li7, Aravind Haripriya8, Satoko Nakano9, Steffen Uebe10, Jeffrey M. Harder11, Anita S.Y. Chan1,2, Mei Chin Lee1, Kathryn P. Burdon12,13, Yury S. Astakhov14, Khaled K. Abu-Amero15,16, Juan C. Zenteno17,18, Yildirim Nilgün19, Tomasz Zarnowski20, Mohammad Pakravan21, Leen Abu Safieh22, Liyun Jia23, Ya Xing Wang24, Susan Williams25, Daniela Paoli26, Patricio G Schlottmann27, Lulin Huang28,29,30, Kar Seng Sim7, Jia Nee Foo7, Masakazu Nakano31, Yoko Ikeda32, Rajesh S Kumar33, Morio Ueno32, Shin-ichi Manabe34, Ken Hayashi34, Shigeyasu Kazama35, Ryuichi Ideta36, Yosai Mori37, Kazunori Miyata37,38, Kazuhisa Sugiyama39, Tomomi Higashide39, Etsuo Chihara40, Kenji Inoue41, Satoshi Ishiko42, Akitoshi Yoshida43, Masahide Yanagi44, Yoshiaki Kiuchi44, Makoto Aihara45, Tsutomu Ohashi46, Toshiya Sakurai47, Takako Sugimoto38, Hideki Chuman38, Fumihiko Matsuda48, Kenji Yamashiro49, Norimoto Gotoh49, Masahiro Miyake48,49, Sergei Y. Astakhov14, Essam A. Osman15, Saleh A. Al-Obeidan15, Ohoud Owaidhah21, Leyla Al-Jasim21, Sami Al Shahwan21, Rhys A. Fogarty12, Paul Leo50, Yaz Yetkin19, Çilingir Oguz19, Mozhgan Rezaei Kanavi21, Afsaneh Naderi Beni21, Shahin Yazdani21, Evgeny L. Akopov14, Kai-Yee Toh7, Gareth R Howell11, Andrew C. Orr51, Yufen Goh7, Wee Yang Meah7, Su Qin Peh7, Ewa Kosior-Jarecka20, Urszula Lukasik20, Mandy Krumbiegel10, Eranga N Vithana1, Tien Yin Wong1,2,3, Yutao Liu52,53, Allison E. Ashley Koch52, Pratap Challa6, Robyn M Rautenbach54, David A. Mackey55, Alex W Hewitt13,56, Paul Mitchell57, Jie Jin Wang57, Ari Ziskind54, Trevor Carmichael25, Rangappa Ramakrishnan8, Kalpana Narendran8, Rangaraj Venkatesh8, Saravanan Vijayan58, Peiquan Zhao59, Xueyi Chen60, Dalia Guadarrama-Vallejo17,18, Ching Yu Cheng1,3, Shamira A Perera1,2, Rahat Husain1,2, Su-Ling Ho61, Ulrich-Christoph Welge-Luessen62, Christian Mardin62, Ursula Schloetzer-Schrehardt62, Axel M. Hillmer63, Stefan Herms64,65,66,67, Susanne Moebus68, Markus M. Nothen64,65, Nicole Weisschuh69, Rohit Shetty33, Arkasubhra Ghosh1,70, Yik Ying Teo7,71, Matthew A Brown50, Ignacio Lischinsky72, The Blue Mountains Eye Study GWAS team73, Wellcome Trust Case Control Consortium 273, Jonathan G Crowston56,74, Michael Coote56,74, Bowen Zhao22, Jinghong Sang23, Nihong Zhang23, Qisheng You24, Vera Vysochinskaya75, Panayiota Founti76, Anthoula Chatzikyriakidou77, Alexandros Lambropoulos77, Eleftherios Anastasopoulos76, Anne L Coleman78, M Roy Wilson79, Douglas J Rhee80, Jae Hee Kang81, Inna May-Bolchakova82, Steffen Heegaard83,84, Kazuhiko Mori32, Wallace L.M. Alward85,86, Jost B Jonas87, Liang Xu24, Jeffrey M Liebmann88, Balram Chowbay89, Elke Schaeffeler90, Matthias Schwab90,91,92, Fabian Lerner93, Ningli Wang23, Zhenglin Yang28,29,30, Paolo Frezzotti94, Shigeru Kinoshita32, John H. Fingert85,86, Masaru Inatani95, Kei Tashiro31, André Reis10, Deepak P. Edward22,96, Louis R. Pasquale80,81, Toshiaki Kubota9, Janey L. Wiggs80**, Francesca Pasutto10**, Fotis Topouzis76**, Michael Dubina14,75**, Jamie E. Craig12**, Nagahisa Yoshimura49**, Periasamy Sundaresan58**, Simon W.M. John11**, Robert Ritch97**, Michael A Hauser6,52**, Chiea-Chuen Khor3,7**
1. Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751
2. Singapore National Eye Center, 11 Third Hospital Avenue, Singapore 168751
3. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore.
4. Ozaki Eye Hospital, 1-15, Kamezaki, Hyuga, Miyazaki 883-0066 Japan
5. Mizoguchi Eye Hospital, 6-13 Tawara-machi, Sasebo, Nagasaki, Japan 857-0016
6. Department of Ophthalmology, Duke University Eye Center, Durham, NC
7. Division of Human Genetics, Genome Institute of Singapore
8. Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, India
9. Department of Ophthalmology, Oita University Faculty of Medicine
10. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
11. The Howard Hughes Medical Institute, the Jackson Laboratory 600 Main Street, Bar Harbor, ME 04609
12. Department of Ophthalmology, Flinders University, Adelaide, SA, Australia
13. Menzies Institute for Medical Research, University of Tasmania
14. Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, 6/8 L’va Tolstogo Street, 197022 St. Petersburg, Russia
15. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
16. Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, FL, USA
17. Genetics Department, Institute of Ophthalmology “Conde de Valenciana”, Mexico
18. Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico
19. Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Eskisehir, Turkey
20. Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland, Chmielna 1, 20-079 Lublin, Poland
21. Ophthalmic Research Center, Ophthalmology department, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
22. King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia
23. Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China
24. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China
25. Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa
26. Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy
27. Organización Médica de Investigación, Uruguay 725 – PB, Buenos Aires (C1015ABO) Argentina
28. Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, China.
29. School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
30. Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China
31. Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
32. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
33. Glaucoma services, Narayana Nethralaya Eye Hospital, 121/C,Chord Road,Rajajinagar, 1st R Block, Bangalore 560 010, India.
34. Hayashi Eye Hospital, 4-23-35, Hakataekimae, Hakata-ku, Fukuoka, Japan
35. Shinjo Eye Clinic, 889-1,Mego,Simokitakatamachi,Miyazaki-shi,Miyazaki 880-0035,Japan
36. Ideta Eye Hospital, Kumamoto, Japan.
37. Miyata Eye Hospital, 6-3, Kurahara, Miyakonojo, Miyazaki 885-0051 Japan
38. Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
39. Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
40. Sensho-kai Eye Institute, Minamiyama 50-1, Iseda, Uji, Kyoto 611-0043, Japan
41. Inouye Eye Hospital, Tokyo, Japan
42. Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan
43. Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan
44. Department of Ophthalmology and Visual Science, Hiroshima University, Hiroshima, Japan
45. Yotsuya Shirato Eye Clinic, Tokyo, Japan
46. Ohashi eye center, Kita1-1 Hondori6 Shiroishi-ku Sapporo 003-0027 Japan
47. Tane Memorial Eye Hospital, Osaka.
48. Center for Genomic Medicine/Inserm U.852, Kyoto University Graduate School of Medicine, Kyoto, Japan
49. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
50. University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Qld, Australia.
51. Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Canada
52. Department of Medicine, Duke University Medical Center, Durham, North Carolina
53. Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia.
54. Division of Ophthalmology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa
55. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia
56. Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
57. Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, NSW Australia
58. Department of Genetics, Aravind Medical Research Foundation, Madurai, India.
59. Department of Ophthalmology, Xin Hua Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, No. 1665, Kongjiang Road, Shanghai 200092, China
60. Department of Ophthalmology, the First Affiliated Hospital of Xinjiang Medical University,Urumchi 830054, Xinjiang Uygur Autonomous Region, China
61. National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
62. Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
63. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore
64. Institute of Human Genetics, University of Bonn, Bonn, Germany
65. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
66. Division of Medical Genetics, University Hospital, Basel, Switzerland
67. Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
68. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany
69. University Eye Hospital, Wuerzburg, Germany
70. Genes, Repair and Regeneration in Ophthalmic Workstation Research Lab, Narayana Nethralaya Foundation, Bangalore, India
71. Saw Swee Hock School of Public Health, National University of Singapore, Singapore
72. Centro Oftalmologico Lischinsky, Junin 692, Tucuman (4000) – Argentina
73. A full list of members and affiliations appears in the Supplementary Note.
74. Department of Ophthalmology, University of Melbourne,
75. St. Petersburg Academic University, 8/3 Klopina Street, 194021 St.Petersburg, Russia
76. Department of Ophthalmology, Faculty of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
77. Department of Biology and Genetics, Faculty of Medicine, Aristotle University of Thessaloniki, Greece
78. Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 United States.
79. Wayne State University, Detroit, 48202, United States
80. Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America
81. Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America,
82. Ophthalmology Department, Military Hospital Begin, Paris, France
83. Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark
84. Department of Ophthalmology, Glostrup University Hospital, Glostrup, Denmark.
85. Stephen A. Wynn Institute for Vision Research, University of Iowa, USA.
86. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City
87. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Germany
88. New York University School of Medicine; Manhattan Eye, Ear and Throat Hospital, New York.
89. Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre of Singapore.
90. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University Tuebingen, Germany
91. Department of Clinical Pharmacology, University Hospital, Tuebingen, Germany
92. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany.
93. Fundacion para el Estudio del Glaucoma, Marcelo T de Alvear 2010 - 2A Buenos Aires (C1122AAF) Argentina
94. Department of Surgery, Section of Ophthalmology, University of Siena, Siena, Italy
95. Department of Ophthalmology, Faculty of Medical Science, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Yoshida, Fukui, 910-1193, Japan
96. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
97. Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, United States of America
* These authors contributed equally to this work
** These authors jointly supervised this work
For media queries and clarifications, please contact:
Ms Winnie Lim Head, Office of Corporate Communications Genome Institute of Singapore, A*STAR Tel: +65 6808 8013 Email: limcp2@gis.a-star.edu.sg
Mr Ravi Chandran Corporate Communications Singapore National Eye Centre Tel: +65 6322 8394 Email: ravi.chandran@snec.com.sg
About the Genome Institute of Singapore (GIS)
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 achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards academic, economic and societal impact.
The key research areas at the GIS include Human Genetics, Infectious Diseases, Cancer Therapeutics and Stratified Oncology, Stem Cell and Regenerative Biology, Cancer Stem Cell Biology, Computational and Systems Biology, and Translational Research.
The genomics infrastructure at the GIS is utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.
For more information about GIS, please visit: www.gis.a-star.edu.sg
About the Singapore Eye Research Institute
Established in 1997, SERI is Singapore’s national research institute for ophthalmic and vision research. SERI’s mission is to conduct high impact eye research with the aim to prevent blindness, low vision and major eye diseases common to Singaporeans and Asians. Serving as the research institute of the Singapore National Eye Centre, and directly affiliated to the Yong Loo Lin School of Medicine, National University of Singapore, as well the Duke-NUS Graduate Medical School, SERI undertakes vision research in collaboration with local clinical ophthalmic centres and biomedical research institutions, as well as major eye centres and research institutes throughout the world.
SERI has grown from a founding team of five in 1997 to a faculty of 220, encompassing clinician scientists, scientists, research fellows, PhD students and support staff. This makes SERI one of the largest research institutes in Singapore and the largest eye research institute in Asia-Pacific. The institute has amassed an impressive array of publications totalling 2,100 scientific papers as of November 2014, and has secured 212 external peer-reviewed competitive grants worth $197 million. As of November 2014, SERI’s faculty has been awarded over 300 national and international prizes and filed over 90 patents.
For more information about SERI, visit www.seri.com.sg
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 18 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.
For more information about A*STAR, please visit: www.a-star.edu.sg
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