Genome-wide scanning for genetic markers associated with anti-malarial drugs sensitivity of Plasmodium falciparum isolates from the China-Myanmar border region.

Abstract

Background: Understanding the emergence and spread of anti-malarial resistance, particularly to artemisinin and its partner drugs, is essential for eradicating malaria in worldwide. To identify genetic markers associated with susceptibility to common anti-malarial drugs, the in vitro sensitivities of anti-malarial drugs were evaluated, and a genome-wide association study of Plasmodium falciparum susceptibility in vitro to multiple anti-malarial drugs was conducted.

Methods: Genomic DNA from 34 samples of P. falciparum collected between 2007 and 2010 in the Nabang-Lazan Valley along the China-Myanmar border was extracted and subjected to whole-genome sequencing. The standard SYBR Green I-based fluorescence assay and RSA assay were used to evaluated the in vitro sensitivities of anti-malarial drugs. Plink v1.90 was used to investigate the associations of genome-wide SNP with in vitro sensitivities to anti-malarial drugs.

Results: The proportion of isolates showed reduced-susceptible to CQ,SP,QN,PPQ and PND were 88.24%,92.59%,8.82%,8.82%,5.88%, respectively. 93.54% of isolates showed high level of the IC₅₀ values of CQ have a pfcrt CIETS mutations. The isolates with pfdhfr IRNI, NRNL and IRNL mutations showed high SP IC₅₀ values. SNPs on pfhsp90 and pfevp1 showed significant association with IC₅₀ values of CQ. Of particular interest is the significant association found between a locus on chromosome 13 and the sensitivity to dihydroartemisinin. This locus is situated within the gene encoding the inner membrane complex protein 1F (IMC1F),which has been found to be associated with the kelch13 compartment in schizont stages of P. falciparum.

Conclusions: Multiple genetic markers correlating with anti-malarial drug susceptibility were identified in the study, which provide a reference for further investigations into the association between oxidative stress-mediated activity and anti-malarial drugs susceptibility.