Natural resistance to malaria linked to variation in human red blood cell receptors

First study to identify protective effect of glycophorin gene rearrangements on malaria

Researchers have discovered that protection from the most severe form of malaria is linked with natural variation in human red blood cell genes. A study from the Wellcome Trust Sanger Institute, the Wellcome Trust Centre for Human Genetics and their collaborators has identified a genetic rearrangement of red blood cell glycophorin receptors that confers a 40 per cent reduced risk from severe malaria.

Published in Science, this is the first study to show that large structural variants in human glycophorin genes, which are unusually common in Africa, are protective against malarial disease. It opens a new avenue for research on vaccines to prevent malaria parasites invading red blood cells.

More than 200 million people a year are infected with malaria and the disease caused the deaths of nearly half a million people worldwide in 2015. Transmitted by mosquitoes, the most widespread malarial parasite in Africa is Plasmodium falciparum; it is also the most dangerous.

Plasmodium parasites infect human red blood cells and gain entry via receptors on the cell surface. Previous studies on natural resistance to malaria had implicated a section of human genome near to a cluster of receptor genes. These receptors – glycophorins – are located on the surface of red blood cells and are amongst many receptors that bind Plasmodium falciparum. However, it is only now that they have been shown to be involved in protection against malaria.

Researchers investigated the glycophorin area of the genome in more detail than before using new whole-genome sequence data from 765 volunteers in the Gambia, Burkina Faso, Cameroon and Tanzania. Using this new information they then undertook a study across the Gambia, Kenya and Malawi that included 5310 individuals from the normal population and 4579 people who were hospitalised from severe malaria. They discovered that people who have a particular rearrangement of the glycophorin genes had a 40 per cent reduced risk of severe malaria.

“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.”

Dr Ellen Leffler first author on the paper From the University of Oxford

The hybrid GYPB-A gene is found in a particular rare blood group – part of the MNS* blood group system – where it is known as Dantu. The study found that the GYPB-A Dantu hybrid was present in some people from East Africa, in Kenya, Tanzania and Malawi, but that it was not present in volunteers from West African populations.

“Analysing the DNA sequences allowed us to identify the location of the join between glycophorins A and B in the hybrid gene. It showed us that the sequence is characteristic of the Dantu antigen in the MNS blood group system.”

Dr Kirk Rockett from the University of Oxford

Studying the glycophorin gene cluster to determine differences between the sequences of the three genes with confidence is extremely challenging. This study gives insights into unpicking the region and how it connects to the MNS blood group system and impacts malaria susceptibility.

“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.”

Professor Dominic Kwiatkowski A lead author from the Wellcome Trust Sanger Institute and University of Oxford

More information

Footnote

*The MNS system is a human blood group system based on two genes – glycophorin A and glycophorin B – on chromosome 4. There are 46 antigens in the system; the most common are called M, N, S, s and U.

What is malaria?

• Spread by mosquitos, malaria is one of the most common infectious diseases and a global public health challenge.
• Malaria is a life-threatening disease caused by a parasite that is transmitted through the bite of infected female Anopheles mosquitoes.
• The parasite that causes malaria is a microscopic, single-celled organism called Plasmodium.
• Malaria is predominantly found in the tropical and sub-tropical areas of Africa, South America and Asia.
• It is estimated that there were 198 million cases of malaria in 2013 and 584,000 deaths.
• Around 95% of deaths are in children under the age of five living in Sub-Saharan Africa. However, death rates have fallen globally by 47% since 2000.
• There are six different species of malaria parasite that cause malaria in humans but Plasmodium falciparum and Plasmodium vivax are the most common types.
• If not detected and treated promptly, malaria can be fatal. However, with the right treatment, started early enough, it can be cured.

More information

For more information about malaria please see http://www.yourgenome.org/facts/what-is-malaria

Funding

This work was supported by the Wellcome Trust, the Bill & Melinda Gates Foundation and the Medical Research Council. Please see the paper for further funding.

Participating centres

• Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
• Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
• Medical Research Council Unit, Atlantic Boulevard, Fajara, PO Box 273, The Gambia.
• Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
• Royal Victoria Teaching Hospital, Independence Drive, PO Box 1515, Banjul, The Gambia.
• Centre National de Recherche et de Formation sur le Paludisme (CNRFP), 01 BP 2208 Ouagadougou 01, Burkina Faso.
• University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy.
• Department of Medical Laboratory Sciences, University of Buea, PO Box 63, Buea, South West Region, Cameroon.
• Department of Biochemistry & Molecular Biology, University of Buea, PO Box 63, Buea, South West Region, Cameroon.
• KEMRI-Wellcome Trust Research Programme, PO Box 230-80108, Kilifi, Kenya.
• Nuffield Department of Medicine, NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, UK.
• Faculty of Medicine, Department of Medicine, Imperial College, Exhibition Road, London SW7 2AZ, UK.
• Joint Malaria Programme, Kilimanjaro Christian Medical Centre, PO box 2228, Moshi, Tanzania.
• Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
• National Institute for Medical Research, Mwanza Research Centre, Mwanza City, Tanzania.
• Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Queen Elizabeth Central Hospital, College of Medicine, PO Box 30096, Chichiri, Blantyre 3, Malawi.
• Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
• Blantyre Malaria Project, Queen Elizabeth Central Hospital, College of Medicine, PO Box 30096, Chichiri, Blantyre 3, Malawi.
• College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
• International Blood Group Reference Laboratory, NHS Blood and Transplant, 500 North Bristol Park, Filton, Bristol BS34 7QH, UK.