Dengue is globally the most common mosquito-borne infection after malaria, with an estimated 100 million infections occurring annually. Symptoms range from mild to incapacitating high fever, with potentially life-threatening complications. No vaccine or specific treatments exist for the disease.
In children, severe dengue is characterised by increased vascular permeability, a state in which blood plasma is able to ‘leak’ from blood vessels to surrounding tissues. This is a potentially deadly complication that can lead to dengue shock syndrome – a life-threatening form of hypovolemic shock caused by a decrease in the volume of blood plasma.
Epidemiological studies have suggested that certain populations are more susceptible to severe dengue, implying that some people’s genetic make-up makes them more susceptible to the disease. To test this hypothesis, researchers at the Wellcome Trust Vietnam Research Programme and Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam, together with researchers from the Genome Institute of Singapore, conducted the first ever genome-wide association study to compare the genomes of children with severe dengue against population controls.
Initially, they compared 2008 patients to 2018 controls. They then replicated their findings in an independent follow-up sample of 1737 cases and 2934 controls.
The findings are published today in the journal ‘Nature Genetics’. The researchers identified changes in the DNA code located within two genes – MICB on chromosome 6 and PLCE1 on chromosome 10 – that appeared to increase a child’s susceptibility to dengue shock syndrome.
MICB is known to play a part in the body’s immune system, and the researchers believe that a variant of this gene may affect the activation of natural killer cells or CD8 T-cells, two types of cells that have a key role in combating viral infection. If these cells are not properly functioning, their ability to rid the body of the dengue virus becomes impaired. This hypothesis is consistent with evidence that increased viral loads occur in the tissues of patients with severe dengue.
Mutations in PLCE1 have previously been linked to nephrotic syndrome, a childhood disease characterised by impairment of the normal barrier and blood-filtering functions of cells in the kidney. The researchers believe that PLCE1 might also contribute to the normal functioning of the vascular endothelium (the thin layer of cells that lines the interior surface of blood vessels), with some variants of PLCE1 predisposing an individual to leakage from the blood vessels, the hallmark clinical feature of dengue shock syndrome.
Professor Cameron Simmons, senior author of the study from the Oxford University Clinical Research Unit, Vietnam, said: “Dengue is a potentially life-threatening disease. Our study confirms epidemiological evidence that some people are naturally more susceptible to severe forms of the disease than others. Our findings offer tantalising clues as to why this should be the case and open up new avenues for us to explore to help us understand the disease.”
Dr Khor Chiea Chuen, first author of the study, added: “This study implicates genetic variation in a molecule that activates natural killer cells as a culprit for increased susceptibility to severe dengue. This is surprising as prior to this it was thought that defects in other components of the immune response, such as T-cells, B-cells or dendritic cells, were responsible. However, they did not show up in our large, well-powered genome scan.”
Commenting on the research, Professor Danny Altmann, Head of Pathogens, Immunology and Population Health at the Wellcome Trust, said: “The World Health Organization estimates that two-fifths of the world’s population – 2.5 billion people – are at risk from dengue infection, yet we still do not have any specific treatments or licensed vaccines. This study, the first of its kind for dengue, is a step along the road towards understanding and eventually combating this deadly disease.”
Image: A female Aedes albopictus mosquito, a vector for dengue fever. Credit: Wellcome Images.
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Notes for editors
Chiea Chuen K et al. Genome-wide association study identifies susceptibility loci for Dengue shock syndrome at MICB and PLCE1. Nat Genet 2011 (epub ahead of print).
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.
Combating infectious diseases is one the strategic priorities of the Wellcome Trust. Much of this work is carried out at a local level in regions where disease is endemic. This includes several major overseas programmes, including the Wellcome Trust’s Vietnam Research Programme.
About the Agency for Science, Technology and Research
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.
About Oxford University‘s Medical Sciences Division
Oxford University’s Medical Sciences Division is recognized internationally for its outstanding research and teaching, attracting the brightest minds from all over the world.
It is one of the largest biomedical research centres in Europe, with over 2500 people involved in research and more than 2800 students, and brings in around two-thirds of Oxford University’s external research income. Listed by itself, that would make it the fifth largest university in the UK in terms of research grants and contracts.
A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.
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 and cevelopmental biology, cancer biology and pharmacology, human genetics, infectious diseases, genomic technologies, and computational and 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.