title: A novel locus of resistance to severe malaria in a region of ancient balancing selection.
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.
authors.forename: Gavin
authors.initials: G
authors.lastname: Band
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Chris C A
authors.initials: CC
authors.lastname: Spencer
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D000017:ABO Blood-Group System; D000349:Africa / Q000453:epidemiology; D000818:Animals; D002648:Child; D017124:Conserved Sequence / Q000235:genetics; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D019143:Evolution, Molecular; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006021:Glycophorins / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006790:Host-Parasite Interactions / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000235:genetics* / Q000469:parasitology; D008297:Male; D002679:Pan troglodytes / Q000235:genetics; D010963:Plasmodium falciparum / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics*
chemical_list: D000017:ABO Blood-Group System; D016326:Extracellular Matrix Proteins; C575351:FREM3 protein, human; D006021:Glycophorins