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. 2022 Jun 8;13(1):3307.
doi: 10.1038/s41467-022-30990-5.

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

S Uyoga #  1 , J A Watson #  2   3 , P Wanjiku  4 , J C Rop  4 , J Makale  4 , A W Macharia  4 , S N Kariuki  4 , G M Nyutu  4 , M Shebe  4 , M Mosobo  4 , N Mturi  4 , K A Rockett  5 , C J Woodrow  6   7 , A M Dondorp  6   7 , K Maitland  4   8 , N J White  6   7 , T N Williams  9   10
Affiliations

The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

S Uyoga et al. Nat Commun. .

Abstract

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Case-only genetic association study using 14 targeted variants and three quantitative traits.
a–c Distributions of the three quantitative traits (observed data: parasite density in green; PfHRP2 in purple; ratio PfHRP2/parasites in orange). d Effect estimates (95% confidence intervals) expressed as fold changes on the standardized trait distribution (rescaled to have mean 0 and standard deviation 1).
Fig. 2
Fig. 2. Distributions of plasma PfHRP2 and parasite density across HBB (rs344), ABO (rs8176719), HBA1-2 (α-thalassemia), and FREM3/GYP (rs186873296) genotypes.
Boxplots (center: median; bounds of box: interquartile range; whiskers: 1.5 standard deviations; points: outliers) are based on observed data; the width of each boxplot is proportional to the square root of the number of data points.
Fig. 3
Fig. 3. Distributions of plasma PfHRP2, parasite density, and PfHRP2/parasite ratio across the ATP2B4 genotypes (rs1541255).
Boxplots (center: median; bounds of box: interquartile range; whiskers: 1.5 standard deviations; points: outliers) are based on the observed data; the width of each boxplot is proportional to the square root of the number of data points.
Fig. 4
Fig. 4. Non-weighted versus probabilistically weighted case-control analysis.
Odds-ratios (point estimates and 95% confidence intervals estimated under a logistic regression model) are shown for a case–control analysis for the five major red cell polymorphisms.
See this image and copyright information in PMC

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