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. 2014 Dec;58(12):7390-7.
doi: 10.1128/AAC.03337-14. Epub 2014 Sep 29.

Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response

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Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response

Maria Isabel Veiga et al. Antimicrob Agents Chemother. 2014 Dec.

Abstract

Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance.

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Figures

FIG 1
FIG 1
2D representation of PfMRP2, with the location of the analyzed SNPs and microindels. The structure depicted refers to the reference P. falciparum 3D7 clone sequence, comprising 2,108 aa. Note that the numbering of amino acids follows the 3D7 reference genomic data, independently of the microindel variation observed in the studied Thai set of parasites.
FIG 2
FIG 2
Microindels identified in the Pfmrp2 by sequencing the Thai isolates and aligning the sequences with publicly available sequencing data. The 5 microindels identified were subcategorized as MI variants of type a (the 3D7 reference genomic sequence type); the other types are designated b to l for the variants found among the Thai isolates (N) and the publicly available genomes. Symbols for publicly available genomes: ,ドル Dd2; &, Hb3; #, UGT5.1; §, RAJ116; +, IGH-CR14. Highlighted black boxes denote amino acid positions that are described in the PlasmoDB database (http://www.plasmodb.org) as single nucleotide polymorphisms.
FIG 3
FIG 3
SNPs and microindels and their associations with IC50 values and parasite clearance rates. We used one-way ANOVA to compare associations between IC50s and the presence (+) or absence (−) of the SNP or microindel type. Chi-square analysis was used to compare associations between high (<36-h) or low (>90-h) parasite clearance rates and the presence (+) or absence (−) of the SNP or microindel type. *, P < 0.05 (significant findings are also highlighted in gray, for additional emphasis. #, the number of samples bearing each genotype. Results represent only the analysis for genotypes with allele frequencies of >8%.

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