6 October 2015
A new study reports a novel malaria resistance locus that provides 33% protection against severe malaria. The study published this week in Nature reveals the genome variations in DNA which can help protect African children from developing severe malaria. These findings provide new insights into the host–parasite interactions that are critical in determining the outcome of malaria infection.
The purpose of the research is to assess why some children are better able to resist the illness, in places where malaria is common. To identify the new locus, researchers conducted a large genome-wide association study (GWAS) using data from eight African countries: Kenya, Malawi, The Gambia, Burkina Faso, Mali, Cameroon, Tanzania and Ghana. They first compared the DNA of 5,633 children with severe malaria with the DNA of 5,919 children without severe malaria; then replicated their key findings in a further 14,000 children.
The results show that a newly-discovered locus is near a cluster of genes which code for proteins called ‘glycophorins’ that are involved in the malaria parasite’s invasion of red blood cells. Although many different malaria resistance loci have been postulated over the years, this is one of very few that have stood up to stringent testing in a large multi-centre study; others include the genes for sickle cell and the O blood group.
A particularly strongly-protective variant, or allele, was found most commonly among children in Kenya in East Africa. Having this allele reduces the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied. The difference between populations could be due to the genetic features of the local malaria parasite in East Africa.
Researchers have known for decades that the glycophorin cluster of genes is highly variable, but it was not possible to show that this genetic variation was responsible for protecting people against severe malaria. Now, with improved GWAS methodology, and the ability to collect samples from across different African countries, researchers are better able to understand the complexity in the patterns of DNA and, crucially, accurately measure their effects on an individual’s level of resistance to the disease.
Surprisingly, these DNA variants are also near one of only a handful of locations in the genome where humans and chimpanzees have the same combination of alleles, suggesting they have been around for millions of years – and that balancing selection may be maintaining these variations throughout a long-standing evolutionary battle between humans and malaria parasites.
One way balancing selection arises is when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences. The classic example is the sickle cell gene – people with one copy of the gene are strongly protected against malaria, but those with two copies of the gene develop a life-threatening condition known as sickle-cell disease.
This work is the latest publication to come from MalariaGEN’s Consortial Project 1, an international collaboration which was initiated in 2005, as part of the Grand Challenges in Global Health, and involves partners in several malaria-endemic countries including, including MRC Gambia researchers.
The MRC Unit, Gambia has been part of the MalariaGEN since its inception and have collaborated by providing purified genomic material from children with severe malaria and controls. In this study Kalifa A. Bojang, Muminatou Jallow, and Margaret Pinder were responsible for clinical data and sample collection / processing. Children with severe malaria were recruited on admission to hospital and control samples were obtained from cord blood from recruited mothers giving birth at maternity units. The severe malaria samples formed part of a larger programme of clinical trials on severe malaria and the cord blood samples formed part of the local DNA Bank used for many genetic studies. All individual studies and the provision of samples to MalariaGEN were approved by the approved by the Scientific Coordinating Committee of the MRC Unit Gambia and the Joint Gambia Government/Medical Research Council Ethics Committee.
Find more: http://dx.doi.org/10.1038/nature15390
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The Malaria Genomic Epidemiology Network (MalariaGEN) is an international community of researchers working to understand how genetic variation in humans, Plasmodium parasites, and Anopheles mosquitoes affects the biology and epidemiology of malaria — and using this knowledge to develop new tools to inform malaria control. The network currently involves researchers in more than 40 malaria-endemic countries with a coordinating centre at Oxford University and the Wellcome Trust Sanger Institute. www.malariagen.net
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