Journal Article

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

Rockett, Kirk A, Band, Gavin, Spencer, Chris C A, Kwiatkowski, Dominic P

2015

Overview

A multi-centre genome-wide association study of severe malaria in African children uncovers a new resistance locus close to a cluster of genes encoding glycophorins, which are receptors used by the malaria-causing parasite to invade red blood cells. Gene variants associated with resistance to malaria This multi-centre genome-wide association study of severe malaria in more than 11,000 African children uncovers a new variant associated with resistance to malaria that is close to a cluster of genes encoding glycophorins — membrane receptors used by the Plasmodium falciparum parasite to invade red blood cells. Interestingly, the variant is linked to polymorphisms previously found to have been maintained for millions of years, based on genome analysis of humans and chimpanzees. 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 1 , 2 , 3 . 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 4 . Taken together with previous observations on the malaria-protective role of blood group O 1 , 2 , 3 , 5 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/43 / 45/61 / 45/77 / 631/181/457/649 / 631/208/205/2138 / 631/326/417/2546 / ABO Blood-Group System / Africa - epidemiology / Animals / Child / Conserved Sequence - genetics / Disease susceptibility / Erythrocyte Membrane - metabolism / Erythrocytes / Erythrocytes - metabolism / Erythrocytes - parasitology / Evolution, Molecular / Extracellular Matrix Proteins - genetics / Female / Gene expression / Genetic aspects / Genetic diversity / Genetic polymorphisms / Genetic Predisposition to Disease - genetics / Genome-Wide Association Study / Genomes / Glycophorins - genetics / Haplotypes / Haplotypes - genetics / Host-Parasite Interactions - genetics / Humanities and Social Sciences / Humans / Identification and classification / Immunology / letter / Ligands / Malaria / Malaria, Falciparum - epidemiology / Malaria, Falciparum - genetics / Malaria, Falciparum - parasitology / Male / multidisciplinary / Pan troglodytes - genetics / Parasites / Plasmodium falciparum - physiology / Polymorphism, Single Nucleotide - genetics / Population / Principal components analysis / Risk factors / Science / Selection, Genetic - genetics / Vector-borne diseases