It has long been known that environmental factors such as malnutrition and poor hygiene play an important role in governing an individuals susceptibility to infectious diseases. In a paper recently published in the New England Journal of Medicine (NEJM) , a team from Professor Adrian Hill's laboratory at the Wellcome Trust Centre for Human Genetics (WTCHG), working with colleagues from Singapore's Agency for Science, Technology and Research (A*STAR), the National University Health System in Singapore and the National University of Singapore, demonstrate that genetics also plays a key role. Their research reveals a striking association between a single gene, CISH, and an increased risk of susceptibility to infectious diseases such as tuberculosis, malaria and serious bacterial infections of the blood, or bacteraemia. CISH encodes for a protein that is involved in the immune response to infectious diseases.
To reach their conclusions the team analysed genetic variants in the CISH gene to look for differences between healthy controls and those with tuberculosis, malaria and bacteraemia. In all 8402 individuals from The Gambia, Hong Kong, Kenya, Malawi and Vietnam were enrolled in the study, making it one of the largest genetic studies of infectious diseases to date. They found that five single-nucleotide polymorphisms (SNPs) in the CISH gene played a key role in governing susceptibility, and that having just one of these SNPs increased susceptibility to disease by 18%. 'This work is unveiling the mechanisms behind infectious disease vulnerability,' says Hill. 'Studying these mechanisms could lead to the design of better vaccines and drugs in the future. The results also tell us that CISH is well worth following up with more research to understand better how the immune system responds to infectious diseases.'
Follow up genome-wide association studies using high throughput screening technologies, and funded by the Wellcome Trust Case Control Consortium, are already underway with groups from Hill's laboratory working in collaboration with researchers at the MRC Laboratories, Gambia, The Kenya Medical Research Institute, and the Wellcome Trust Programme Centre for Geographic Medicine Research in Kilifi, Kenya. In contrast to the CISH project, which concentrated on a single gene, these studies are applying a 'brute force' approach to look at SNPs across the entire genome. 'Instead of just looking at single genes that we think may be associated with a disease, we are globally exploring the entire complement of chromosomes to get an idea of the relative importance of different regions of the genome in susceptibility of specific infectious diseases,' reports Dr Fred Vannberg, a post doctoral researcher in Hill's lab and a co-author of the NEJM paper . 'By using one gene chip per person in our studies we are able to gather information for all the 23 chromosomes in one shot.' The first follow up study, which examined genes related to susceptibility to tuberculosis and involved studying 500,000 SNPs across the genome, is nearly complete. A similar study on bacteraemia is now in progress. A study of HIV susceptibility is also planned. 'These larger studies are part of our continued efforts to understand infectious diseases,' explains Vannberg. 'We hope that knowledge gained can also be applied to improve our lab's work on vaccines."
For more information on Prof Hill's research, click here.