High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia

Abstract

In western Cambodia, malaria parasites clear slowly from the blood after treatment with artemisinin derivatives, but it is unclear whether this results from parasite, host, or other factors specific to this population. We measured heritability of clearance rate by evaluating patients infected with identical or nonidentical parasite genotypes, using methods analogous to human twin studies. A substantial proportion (56%-58%) of the variation in clearance rate is explained by parasite genetics. This has 2 important implications: (1) selection with artemisinin derivatives will tend to drive resistance spread and (2) because heritability is high, the genes underlying parasite clearance rate may be identified by genome-wide association.

Trial registration: ClinicalTrials.gov NCT00493363.

Figure 1

Clearance profiles of Clonally Identical parasites. We plotted natural log of parasite density against time post treatment. Each of the nine panels shows clearance profiles for single CI genotype sampled from multiple patients. CI genotypes 1 and 2 (panel a and b) have higher clearance rate than other CI genotypes (Fig 2c). Fit of clearance profiles to a linear model is detailed in Table S2.

Figure 2

(a) Clustering of parasites based on genetic similarity. We constructed a UPGMA tree from a pairwise matrix of allele-sharing (1 – proportion of shared alleles) between parasites using PHYLIP. We observed nine independent 18-locus genotypes that were present in multiple patients. The clonally identical genotypes analyzed are marked in blue text, while the grey squares indicate the numbers of patients infected with each clone. Clone 9 was excluded from the analysis as clearance data from one of the two patients fitted poorly with a linear model. Inclusion of this clone did not alter the results. (b) Distribution of clearance rate (CR) in Cambodian parasites. The majority of parasites show slow CR, while 10% show clearance rates similar to those in Western Thailand. Error bars show 1 s.d. around the estimate of CR. (c) Clearance rates of clonally identical parasites. Clonally identical genotypes are marked 1-8 and are shown on the x-axis (see panel (a)) while CR is shown on the y-axis. Clones 1 and 2 show consistently faster clearance than the other 6.