Resistance to severe malaria identified in gene variants

A gene variant which gives protection against the most dangerous form of malaria has been identified.

Researchers from the University of Oxford, the Wellcome Trust Sanger Institute in the UK, and their collaborators, have identified a naturally occurring genetic rearrangement which reduces the risk of severe malaria by 40 percent. The affected genes code for proteins known as glycophorin receptors, expressed on the surface of red blood cells.

Dr Ellen Leffler at the University of Oxford, first author on the paper published in Science, said: '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.'

Malaria is caused by parasites of the Plasmodium family, which invade red blood cells and reproduce inside them. In 2015, 212 million cases of malaria occurred and 429,000 people died of the disease, with young children most affected, according to the World Health Organization. The identified genetic variant makes people resistant to Plasmodium falciparum, which is the most dangerous and lethal form of the parasite.

The researchers analysed the genomes of more than 12,000 people in the course of the study. Having previously identified that modifications in the chromosomal region where the glycophorin genes are found might protect against malaria, they first constructed a 'reference' set of around 3000 genomes from around the world (more than 1200 of which were of African origin), to examine normal levels of variation. They then examined a database of genomes of more than 10,000 people from Gambia, Kenya, and Malawi, of whom around half had suffered from severe malaria, to identify specific changes in this chromosomal region in the people who had not caught the disease.

This led to the identification of the genetic variant known as DUP4, a rearrangement of the glycophorin genes on chromosome 4, which was present at substantially high frequency in east African populations compared to the reference panel. The people who have this mutation were 40 percent less likely to catch the disease. This rearrangement leads to the expression of modified glycophorin proteins on the surface of red blood cells – the authors speculate that this may make it more difficult for the parasite to gain access to red blood cells, although how and why remains unknown. Interestingly, the variant was present in east, but not west African populations, suggesting that it might have evolved quite recently.

Professor Dominic Kwiatkowski, a lead author on the study, said: '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 invades red blood cells. This could also help us discover novel parasite weaknesses that could be exploited in future interventions against this deadly disease.'