Malaria protection due to sickle haemoglobin depends on parasite genotype

Gavin Band (), Ellen M. Leffler, Muminatou Jallow, Fatoumatta Sisay-Joof, Carolyne M. Ndila, Alexander W. Macharia, Christina Hubbart, Anna E. Jeffreys, Kate Rowlands, Thuy Nguyen, Sónia Gonçalves, Cristina V. Ariani, Jim Stalker, Richard D. Pearson, Roberto Amato, Eleanor Drury, Giorgio Sirugo, Umberto d’Alessandro, Kalifa A. Bojang, Kevin Marsh, Norbert Peshu, Joseph W. Saelens, Mahamadou Diakité, Steve M. Taylor, David J. Conway, Thomas N. Williams, Kirk A. Rockett () and Dominic P. Kwiatkowski ()
Additional contact information
Gavin Band: University of Oxford
Ellen M. Leffler: Wellcome Sanger Institute
Muminatou Jallow: Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine
Fatoumatta Sisay-Joof: Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine
Carolyne M. Ndila: KEMRI-Wellcome Trust Research Programme
Alexander W. Macharia: KEMRI-Wellcome Trust Research Programme
Christina Hubbart: University of Oxford
Anna E. Jeffreys: University of Oxford
Kate Rowlands: University of Oxford
Thuy Nguyen: Wellcome Sanger Institute
Sónia Gonçalves: Wellcome Sanger Institute
Cristina V. Ariani: Wellcome Sanger Institute
Jim Stalker: Wellcome Sanger Institute
Richard D. Pearson: Wellcome Sanger Institute
Roberto Amato: Wellcome Sanger Institute
Eleanor Drury: Wellcome Sanger Institute
Giorgio Sirugo: Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine
Umberto d’Alessandro: Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine
Kalifa A. Bojang: Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine
Kevin Marsh: KEMRI-Wellcome Trust Research Programme
Norbert Peshu: KEMRI-Wellcome Trust Research Programme
Joseph W. Saelens: Duke University School of Medicine
Mahamadou Diakité: University of Sciences, Techniques, and Technologies of Bamako
Steve M. Taylor: Duke University School of Medicine
David J. Conway: Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine
Thomas N. Williams: KEMRI-Wellcome Trust Research Programme
Kirk A. Rockett: University of Oxford
Dominic P. Kwiatkowski: University of Oxford

Nature, 2022, vol. 602, issue 7895, 106-111

Abstract: Abstract Host genetic factors can confer resistance against malaria1, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member2–4 PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

Date: 2022
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DOI: 10.1038/s41586-021-04288-3

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