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Protective Effect of Human Sickle Hemoglobin Against Malaria Varies with Parasite Genotype

Plasmodium falciparum

NEW YORK — Malaria-causing parasites appear to be countering the protective effect conferred by the sickle hemoglobin mutation found among some human populations, a new analysis has found.

There are about 241 million cases of malaria each year, which in 2020 led to 627,000 deaths, mostly in sub-Saharan Africa. By analyzing samples of the malaria parasite Plasmodium falciparum obtained from thousands of children in Gambia and Kenya with severe malaria, a University of Oxford-led team found that children with the sickle hemoglobin, or HbS, mutation tended to have malaria caused by P. falciparum that harbor three particular genetic variants. These variants, which are in linkage disequilibrium, seem to counter the otherwise protective effect of HbS, as the team reported in Nature on Thursday.

"It's well known that the sickle hemoglobin mutation has evolved under selection pressure from malaria — it is strongly protective if you inherit one copy, so it has been driven to reasonable frequencies in places like sub-Saharan African where mortality from malaria is high," first author Gavin Band from Oxford said in an email. "Our new results show that the parasite appears, in turn, to have adapted to the HbS mutation."

He and his colleagues sequenced P. falciparum samples collected between 1995 and 2009 from Gambian and Kenyan children with severe malaria, and generated genotyping data for both the parasites and affected children for 4,171 samples.

In a joint analysis of host and parasite genetic variation, the researchers uncovered a strong association between HbS and three regions of the P. falciparum genome, which they dubbed Pfsa1, Pfsa2, and Pfsa3.

Most of the children with an HbS genotype had malaria caused by a parasite with a Pfsa+ allele, and the researchers' data indicated that there was little evidence that HbS provided protection against severe malaria if the infecting parasites harbored Pfsa1+, Pfsa2+, and Pfsa3+ alleles. It did, though, still provide protection against severe malaria caused by Pfsa- parasites.

The Pfsa1+, Pfsa2+, and Pfsa3+ alleles are present at similar frequencies throughout Kenya, while in Gambia, Pfsa2+ was present at lower frequency, as compared to Pfsa1+ and Pfsa3+. The frequency of these alleles varied throughout Africa and were rare outside of Africa, the researchers noted, adding that the Pfsa+ alleles correlated with the frequency of the HbS genotype among people.

The three alleles are further in linkage disequilibrium, even the allele that is located on a different chromosome. This LD link, the researchers noted, was not explained by population structure or other covariate and was also observed in other populations in MalariaGEN.

Exactly why or how this is maintained is unclear, Band said, but he added that there are two main possibilities. First, it could be an effect of population structure associated with HbS, though they did not have any evidence supporting that notion. The other possibility is that the variants are indeed co-inherited and that there is epistasis between them.

"I think the importance of these results stems from the fact that so much of this is unknown — the results point at aspects of parasite biology that are clearly important to the parasites, but that currently we don't really know much about at all," Band said. "So, our results open up an area of investigation that might generate new insights into parasite biology."

Band and his colleagues are now conducting further genetic surveys to gain a better understanding of the Pfsa+ alleles, as well as performing laboratory studies to determine how the alleles contribute to malaria resistance — one allele includes variants within PfACS8 on chromosome 2, an acyl-CoA synthetase family member, while another is within a region on chromosome 2 and the third is in a structural variation-containing region on chromosome 11. They are also working to understand how natural selection has shaped the loci and how the alleles have changed over time.