A novel locus of resistance to severe malaria in a region of ancient balancing selection

Gavin Band, Kirk A. Rockett, Chris C.A. Spencer, Dominic P. Kwiatkowski, Quang Si Le, Geraldine M. Clarke, Katja Kivinen, Ellen M. Leffler, Victoria Cornelius, David J. Conway, Thomas N. Williams, Terrie Taylor, Kalifa A. Bojang, Ogobara Doumbo, Mahamadou A. Thera, David Modiano, Sodiomon B. Sirima, Michael D. Wilson, Kwadwo A. Koram, Tsiri AgbenyegaEric Achidi, Kevin Marsh, Hugh Reyburn, Chris Drakeley, Eleanor Riley, Malcolm Molyneux, Muminatou Jallow, Margaret Pinder, Ousmane B. Toure, Salimata Konate, Sibiri Sissoko, Edith C. Bougouma, Valentina D. Mangano, Lucas N. Amenga-Etego, Anita K. Ghansah, Abraham V.O. Hodgson, Michael D. Wilson, Daniel Ansong, Anthony Enimil, Jennifer Evans, Tobias O. Apinjoh, Alexander Macharia, Carolyne M. Ndila, Charles Newton, Norbert Peshu, Sophie Uyoga, Alphaxard Manjurano, David Kachala, Vysaul Nyirongo, Daniel Mead, Eleanor Drury, Sarah Auburn, Susana G. Campino, Bronwyn MacInnis, Jim Stalker, Emma Gray, Christina Hubbart, Anna E. Jeffreys, Kate Rowlands, Alieu Mendy, Rachel Craik, Kathryn Fitzpatrick, Sile Molloy, Lee Hart, Robert Hutton, Angeliki Kerasidou, Kimberly J. Johnson

Research output: Contribution to journalArticle

Abstract

The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio= 0.67, 95% confidence interval= 0.60-0.76, P value= 9.5× 10-11) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees. Taken together with previous observations on the malaria-protective role of blood group O, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host-parasite interactions that are critical in determining the outcome of malaria infection.

Original languageEnglish
Pages (from-to)253-257
Number of pages5
JournalNature
Volume526
Issue number7572
DOIs
Publication statusPublished - 2015
Externally publishedYes

Fingerprint Dive into the research topics of 'A novel locus of resistance to severe malaria in a region of ancient balancing selection'. Together they form a unique fingerprint.

Cite this