Abstract:
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Background: Resistance 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.
Methods: 3721 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.
Results: An 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.
Conclusions: The 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. |