Variation in red blood cell receptors may confer malaria resistance

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Researchers have uncovered variations in human red blood cell receptor glycophorin that appear to confer natural resistance to severe malaria, reducing the risk by 40%.

The collaborative study, which included partners such as the Wellcome Trust Sanger Institute (Cambridge, UK), is the first to identify a genetic rearrangement of red blood cell glycophorin receptors that is protective against malaria – potentially opening new avenues for vaccine development.

During an infection, Plasmodium parasites utilize receptors on the cell surface to gain entry to human red blood cells. Previously, reports on natural resistance to malaria have implicated a section of the genome near to a cluster of receptor genes.

In this study, published recently in Science, the team utilized whole-genome sequence data from 756 individuals in Gambia, Burkina Faso, Cameroon and Tanzania to investigate the glycophorin region of the genome. They identified a range of copy number variants affecting receptor genes GYPA and GYPB.

The team then studied 9889 individuals 4579 of which were hospitalized from severe malaria. They discovered that a complex rearrangement, involving the loss of GYPB and gain of two GYPB-A hybrid genes, conferred a 40% reduction in the risk of severe malaria.

Author Ellen Leffler, from the University of Oxford (UK), commented: “In this new study we found strong evidence that variation in the glycophorin gene cluster influences malaria susceptibility. We found some people have a complex rearrangement of GYPA and GYPB genes, forming a hybrid glycophorin, and these people are less likely to develop severe complications of the disease.”

Lead author Dominic Kwiatkowski, from the Wellcome Trust Sanger Institute and University of Oxford, concluded: “We are starting to find that the glycophorin region of the genome has an important role in protecting people against malaria. Our discovery that a specific variant of glycophorin invasion receptors can give substantial protection against severe malaria will hopefully inspire further research on exactly how Plasmodium falciparum invade red blood cells. This could also help us discover novel parasite weaknesses that could be exploited in future interventions against this deadly disease.”

Sources:  Leffler EM, Band G, Busby GB et al. Resistance to malaria through structural variation of red blood cell invasion receptors. Science. doi:10.1126/science.aam6393 (2017) (Epub ahead of print); www.ox.ac.uk/news/2017-05-19-red-blood-cell-variation-linked-natural-malaria-resistance

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