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Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance.

Veiga MI, Ferreira PE, Jörnhagen L, Malmberg M, Kone A, Schmidt BA, Petzold M, Björkman A, Nosten F, Gil JP - PLoS ONE (2011)

Bottom Line: The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility.A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine.Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

View Article: PubMed Central - PubMed

Affiliation: Malaria Research Lab, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Isabel.veiga@ki.se

ABSTRACT
Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The pfcrt, pfmdr1 and pfmrp1 genes were sequenced from a set of P.falciparum field isolates from the Thai-Myanmar border. In vitro drug susceptibility to artemisinin, dihydroartemisinin, mefloquine and lumefantrine were assessed. Positive correlations were seen between the in vitro susceptibility responses to artemisinin and dihydroartemisinin and the responses to the arylamino-alcohol quinolines lumefantrine and mefloquine. The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility. A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine. Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

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Significant association of pfmdr1 copy number variation and in vitro IC50's for ART, MQ and LUM.Significant relationship between average in vitro drugs tested IC50's and pfmdr1 CNV polymorphism. Data described in Table S2. <1.5: 1 gene copy of pfmdr1 (#22 isolates). >1.5: 2 and 3 gene copies of pfmdr1 (#24 isolates). T-test statistics was applied. P value <0.0042 is consider significant after Bonferroni correction. Error bars represent SE.
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pone-0020212-g002: Significant association of pfmdr1 copy number variation and in vitro IC50's for ART, MQ and LUM.Significant relationship between average in vitro drugs tested IC50's and pfmdr1 CNV polymorphism. Data described in Table S2. <1.5: 1 gene copy of pfmdr1 (#22 isolates). >1.5: 2 and 3 gene copies of pfmdr1 (#24 isolates). T-test statistics was applied. P value <0.0042 is consider significant after Bonferroni correction. Error bars represent SE.

Mentions: Since all isolates had the same haplotype for the pfcrt gene, a possible association could not be assessed between the pfcrt SNPs and IC's values. As previously observed [8], [10], [16], [25], and herein confirmed, an increased gene copy number of pfmdr1 was clearly associated with higher IC50's for MQ, LUM and ART (P<0.0042) (Table 1, Figure 2). From the seven SNPs found in pfmdr1, only one, F1226Y, was found to be associated with decreased sensitivity to ART, MQ and LUM IC50 and IC90 (Table 1, Figure 3). The average IC50 (±SE) of the pfmdr1 1226Y allele was 10.09(±1.12), 135.18(±14.57), and 17.77(±1.95) nM, values significantly higher compared with the non-carriers: 5.43(±0.98), 73.06(±14.08) and 9.47(±1.90) nM, for each drug, respectively. Among the 11 SNPs found in pfmrp1 (Table 2), F1390I was documented to significantly modulate the in vitro drug response phenotypes (Table 1). Carriers of the F1390 allele were less susceptible to ART, MQ and LUM, with average IC50's of 8.96(±0.92), 121.71(±12.17) and 15.56(±1.71) nM, compared to 1390I carriers with values of 3.30(±0.86), 37.25 (±9.31) and 6.08(±1.87) nM, respectively (Figure 4). Interestingly, even though pfmdr1 F1226Y and pfmrp1 F1390I alleles have very similar association profiles, both seem to represent independent actions, as they were not found together in the same Thai isolate in more instances than would randomly be expected (P>0.05).


Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance.

Veiga MI, Ferreira PE, Jörnhagen L, Malmberg M, Kone A, Schmidt BA, Petzold M, Björkman A, Nosten F, Gil JP - PLoS ONE (2011)

Significant association of pfmdr1 copy number variation and in vitro IC50's for ART, MQ and LUM.Significant relationship between average in vitro drugs tested IC50's and pfmdr1 CNV polymorphism. Data described in Table S2. <1.5: 1 gene copy of pfmdr1 (#22 isolates). >1.5: 2 and 3 gene copies of pfmdr1 (#24 isolates). T-test statistics was applied. P value <0.0042 is consider significant after Bonferroni correction. Error bars represent SE.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102103&req=5

pone-0020212-g002: Significant association of pfmdr1 copy number variation and in vitro IC50's for ART, MQ and LUM.Significant relationship between average in vitro drugs tested IC50's and pfmdr1 CNV polymorphism. Data described in Table S2. <1.5: 1 gene copy of pfmdr1 (#22 isolates). >1.5: 2 and 3 gene copies of pfmdr1 (#24 isolates). T-test statistics was applied. P value <0.0042 is consider significant after Bonferroni correction. Error bars represent SE.
Mentions: Since all isolates had the same haplotype for the pfcrt gene, a possible association could not be assessed between the pfcrt SNPs and IC's values. As previously observed [8], [10], [16], [25], and herein confirmed, an increased gene copy number of pfmdr1 was clearly associated with higher IC50's for MQ, LUM and ART (P<0.0042) (Table 1, Figure 2). From the seven SNPs found in pfmdr1, only one, F1226Y, was found to be associated with decreased sensitivity to ART, MQ and LUM IC50 and IC90 (Table 1, Figure 3). The average IC50 (±SE) of the pfmdr1 1226Y allele was 10.09(±1.12), 135.18(±14.57), and 17.77(±1.95) nM, values significantly higher compared with the non-carriers: 5.43(±0.98), 73.06(±14.08) and 9.47(±1.90) nM, for each drug, respectively. Among the 11 SNPs found in pfmrp1 (Table 2), F1390I was documented to significantly modulate the in vitro drug response phenotypes (Table 1). Carriers of the F1390 allele were less susceptible to ART, MQ and LUM, with average IC50's of 8.96(±0.92), 121.71(±12.17) and 15.56(±1.71) nM, compared to 1390I carriers with values of 3.30(±0.86), 37.25 (±9.31) and 6.08(±1.87) nM, respectively (Figure 4). Interestingly, even though pfmdr1 F1226Y and pfmrp1 F1390I alleles have very similar association profiles, both seem to represent independent actions, as they were not found together in the same Thai isolate in more instances than would randomly be expected (P>0.05).

Bottom Line: The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility.A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine.Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

View Article: PubMed Central - PubMed

Affiliation: Malaria Research Lab, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Isabel.veiga@ki.se

ABSTRACT
Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The pfcrt, pfmdr1 and pfmrp1 genes were sequenced from a set of P.falciparum field isolates from the Thai-Myanmar border. In vitro drug susceptibility to artemisinin, dihydroartemisinin, mefloquine and lumefantrine were assessed. Positive correlations were seen between the in vitro susceptibility responses to artemisinin and dihydroartemisinin and the responses to the arylamino-alcohol quinolines lumefantrine and mefloquine. The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility. A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine. Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

Show MeSH
Related in: MedlinePlus