Abstract
BackgroundResistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches.Methods3721 samples from five African countries, which were known to contain genotypically drug resistant parasites, were analysed. These parasites were collected from patients who subsequently failed to clear their infection following drug treatment, as expected, but also from patients who successfully cleared their infections with drug-resistant parasites. 67 human polymorphisms (SNPs) on 17 chromosomes were analysed using Sequenom's mass spectrometry iPLEX gold platform, to identify regions of the human genome, which contribute to enhanced clearance of drug resistant parasites.ResultsAn analysis of all data from the five countries revealed significant associations between the phenotype of ability to clear drug-resistant Plasmodium falciparum infection and human immune response loci common to all populations. Overall, three SNPs showed a significant association with clearance of drug-resistant parasites with odds ratios of 0.76 for SNP rs2706384 (95% CI 0.71-0.92, P = 0.005), 0.66 for SNP rs1805015 (95% CI 0.45-0.97, P = 0.03), and 0.67 for SNP rs1128127 (95% CI 0.45-0.99, P = 0.05), after adjustment for possible confounding factors. The first two SNPs (rs2706384 and rs1805015) are within loci involved in pro-inflammatory (interferon-gamma) and anti-inflammatory (IL-4) cytokine responses. The third locus encodes a protein involved in the degradation of misfolded proteins within the endoplasmic reticulum, and its role, if any, in the clearance phenotype is unclear.ConclusionsThe study showed significant association of three loci in the human genome with the ability of parasite to clear drug-resistant P. falciparum in samples taken from five countries distributed across sub-Saharan Africa. Both SNP rs2706384 and SNP1805015 have previously been reported to be associated with risk of malaria infection in African populations. The loci are involved in the Th1/Th2 balance, and the association of SNPs within these genes suggests a key role for antibody in the clearance of drug-resistant parasites. It is possible that patients able to clear drug-resistant infections have an enhanced ability to control parasite growth.
Highlights
Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease
Individuals aged from 5 months old, with uncomplicated P. falciparum malaria, who were treated with antimalarial drugs including chloroquine, amodiaquine, sulphadoxine-pyrimethamine (SP) and artemisinins according to the policy within each country, were recruited to standard in vivo drug efficacy studies carried out in accordance with WHO protocols [25]
This could be because the data were pooled from five countries with different levels of acquired immunity, and involving different age groups according to the study design chosen
Summary
Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. 85% of cases and 89% of deaths due to malaria are found in sub-Saharan Africa [1]. Over the last decade some African countries have seen a reduction in malaria cases and deaths, probably through increased funding for disease control measures such as the use of insecticide-treated mosquito nets. Parasite resistance to anti-malarial drugs, and mosquito vector resistance to insecticides, remain a major threat to the control of malaria. The partial protection is strain-, stage- and speciesspecific This may account for the observed higher malaria infection in children than in adults, and indicates that the immune status of the host influences the severity of malaria disease and the outcome of the treatment [3]
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