Singapore— An international team of researchers has discovered that genes are linked to humans’ ability to resist typhoid fever. This finding is significant in helping to develop personalised therapies for sufferers of typhoid fever, based on an individual’s genetic code.
The research team, jointly led by A*STAR’s Genome Institute of Singapore (GIS) and the Oxford University Clinical Research Unit (OUCRU) in Vietnam had their findings published in the advanced online issue of Nature Genetics.
Typhoid fever is a disease caused by the bacterium Salmonella typhi and is usually contracted through the consumption of contaminated food or water. Most infected individuals recover without any lasting detriment to their health. However, a number of infected individuals are unable to clear the infection, and develop typhoid fever.
An estimated 21 million cases of typhoid fever and 200,000 deaths occur annually worldwide1. Without therapy, the illness can last up to four weeks, ending in death in up to 25 percent of cases. Increasing resistance to available antimicrobial agents may result in dramatic increases in case-fatality rates. Epidemics and high endemic disease rates have occurred in the Central Asian Republics, the Indian subcontinent, and across Asia and the Pacific Islands.
The scientists compared the genomic profiles of typhoid patients with healthy individuals from Vietnam and Nepal. They found that a genetic variant mapping near the human leukocyte antigen (HLA) locus showed very strong association with resistance to typhoid fever. This locus is responsible for the general activation of the immune response upon contact with invading bacteria.
Co-lead author and principal investigator at the Human Genetics unit in GIS, Dr Khor Chiea Chuen, co-lead author and principal investigator at the Human Genetics unit in GIS, said, “We were very surprised to observe such strong association between an HLA marker and individual susceptibility to typhoid. Current typhoid vaccines are not completely effective. The resistance allele acts like a ‘natural vaccine’, and this discovery by our team could help direct and focus future studies to make a truly efficacious typhoid vaccine.”
It was found that individuals carrying one copy of the DNA sequence associated with resistance showed up to four-fold protection against typhoid fever, while those carrying two copies of the same DNA sequence almost never contracted typhoid. This observation suggests that the outcome of the body’s effort to successfully clear an infection by Salmonella typhi depends on how bacterial components interact with the body’s HLA to produce a robust immune response.
Dr Sarah Dunstan, co-lead author and Senior Research Fellow at the Nossal Institute of Global Health, University of Melbourne, added, “Typhoid fever remains a considerable health burden in many lower income countries in Asia. Our study is the first large-scale, search for human genes that affect a person’s risk of typhoid. We found that carrying a particular form of the HLA-DRB1 gene provides natural resistance against typhoid. The HLA molecules are in general very important because they are able to recognise invading bacteria and turn on the body’s immune system. If we can understand this natural mechanism of disease resistance, then we can use this knowledge to help inform improved vaccine and therapeutic design.” Dr Dunstan was Senior Scientist at the OUCRU in Vietnam at the time of the study.
Dr Guy Thwaites, Director of OUCRU in Vietnam, said, “This important study shows the value of multi-centre, collaborative clinical infectious diseases research in Asia. Many of the participants were recruited to clinical trials investigating the best treatment regimens for typhoid fever in Vietnam and Nepal. These patients also provided their consent for later genetic testing, therefore the trials were not only able to provide answers to key clinical questions, but also – as this paper demonstrates beautifully – answers to fundamental questions about shared disease susceptibility mechanisms in different populations.”
The study is jointly funded by A*STAR and the Wellcome Trust.
Notes to Editor:
The research findings described in the media release can be found in the Nature Genetics journal, under the title, “Variation at HLA-DRB1 is associated with resistance to enteric fever” by Sarah J. Dunstan1-3, Nguyen Thi Hue1,4, Buhm Han5-8, Zheng Li9, Trinh Thi Bich Tram1, Kar Seng Sim9, Christopher M. Parry1,10, Nguyen Tran Chinh11, Ha Vinh11, Nguyen Phu Huong Lan11, Nga Tran Vu Thieu1, Phat Voong Vinh1, Samir Koirala12, Sabina Dongol12, Amit Arjyal12, Abhilasha Karkey12, Olita Shilpakar12, Christiane Dolecek1,2, Jia Nee Foo9, Le Thi Phuong13, Mai Ngoc Lanh13, Tan Do14, Tin Aung15, Do Nu Hon14, Yik Ying Teo16,17, Martin L Hibberd9.18, Katherine L. Anders1,2, Yukinori Okada19,20, Soumya Raychaudhuri6-8,21,22, Cameron P. Simmons1,2,23, Stephen Baker1,2,18, Paul I.W. de Bakker24,25, Buddha Basnyat12, Tran Tinh Hien1, Jeremy J. Farrar1,2, Chiea Chuen Khor9,15,17,26,27.
1. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam
2. Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, OX3 7LJ, United Kingdom
3. Nossal Institute of Global Health, Melbourne School of Population and Global Health, The University of Melbourne, Australia, 3010
4. Faculty of Biology, University of Science, Vietnam National University, Ho Chi Minh City, Vietnam.
5. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
6. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
7. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA
8. Partners Center for Personalized Genetic Medicine, Boston, MA, USA
9. Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore
10. Liverpool School of Tropical Medicine, Liverpool, UK
11. Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam
12. Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
13. Dong Thap Provincial Hospital, Cao Lanh, Dong Thap Province, Vietnam
14. Vietnam National Institute of Ophthalmology, Hanoi, Vietnam
15. Singapore Eye Research Institute, Singapore
16. Department of Statistics and Applied Probability, National University of Singapore, Singapore
17. Saw Swee Hock School of Public Health, National University of Singapore, Singapore
18. London School of Tropical Medicine and Hygiene, London, UK
19. Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
20. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama
21. Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
22. Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
23. Department of Microbiology and Immunology, The University of Melbourne, Australia, 3010
24. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands
25. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CG, Utrecht, the Netherlands Japan
26. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore
27. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore.
For media queries and clarifications, please contact:
For A*STAR:
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
For OUCRU:
Miss Susie Maugham
Grants and Communications Manager
OUCRU
Tel: +84 (0) 1885605035
E mail: smaugham@oucru.org
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
About A*STAR’s 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 OUCRU
The Oxford University Clinical Research Unit (OUCRU) is a large-scale clinical and public health research unit based in Viet Nam. We are hosted by the Hospital of Tropical Diseases (HTD) in Ho Chi Minh City, and the National Hospital for Tropical Diseases (NHTD) in Hanoi. We also have sister units in Kathmandu, and Jakarta. As a Wellcome Trust Major Overseas Programme, we have received considerable support from the Wellcome Trust since our establishment in 1991. Our research covers immunology, host and pathogen genetics, molecular biology, virology, mathematical modelling, bioinformatics, biostatistics and epidemiology. This work is all supported by an extensive Clinical Trials Unit and Data Management Centre compliant with national and international regulations and a comprehensive Management, Finance and Administrative Centre.
For more information about OUCRU, please visit: www.oucru.org
1 Source: Data from Centers for Disease Control and Prevention:
http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/technical.html
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