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 member2–4PfACS8 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.
Highlights
This is a PDF file of a peer-reviewed paper that has been accepted for publication
Human populations in Africa have acquired a high frequency of sickle haemoglobin (HbS) and other erythrocyte polymorphisms that provide protection against the severe symptoms of Plasmodium falciparum (Pf) infection[1,5], while P. falciparum populations have evolved a complex repertoire of genetic variation to evade the human immune system and to resist antimalarial drugs[6,7]
We further examined the effect of adjusting for covariates in our data, including human and parasite principal components (PCs) reflecting population structure, year of sampling, clinical type of severe malaria and technical features related to sequencing (Extended Data Figure 3)
Summary
Human populations in Africa have acquired a high frequency of sickle haemoglobin (HbS) and other erythrocyte polymorphisms that provide protection against the severe symptoms of Plasmodium falciparum (Pf) infection[1,5], while P. falciparum populations have evolved a complex repertoire of genetic variation to evade the human immune system and to resist antimalarial drugs[6,7] This raises the basic question: are there genetic forms of P. falciparum that can overcome the human variants that confer resistance to this parasite?. To address this question, we analysed both host and parasite genome variation in samples from 5,087 Gambian and Kenyan children with severe malaria due to P. falciparum (Extended Data Figure 1, Supplementary Figure 1 and Methods). R were observed at a number of other loci, including a potential association between GCNT1 in the host and PfMSP4 in the parasite and associa-
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