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The MSPDBL2 codon 591 polymorphism is associated with lumefantrine in vitro drug responses in Plasmodium falciparum isolates from Kilifi, Kenya.

Ochola-Oyier LI, Okombo J, Mwai L, Kiara SM, Pole L, Tetteh KK, Nzila A, Marsh K - Antimicrob. Agents Chemother. (2014)

Bottom Line: The mechanisms of drug resistance development in the Plasmodium falciparum parasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear.We assessed the polymorphisms of Pfmspdbl2 for associations with LUM activity in a Kenyan population.MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P = 0.04).

View Article: PubMed Central - PubMed

Affiliation: Kenya Medical Research Institute/Wellcome Trust Collaborative Research Program, Kilifi, Kenya liochola@kemri-wellcome.org.

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Pfmspdbl2 codon 591 (n = 46) S allele is associated with reduced susceptibility to LUM (P = 0.035). The horizontal lines indicate the median drug IC50s.
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Figure 2: Pfmspdbl2 codon 591 (n = 46) S allele is associated with reduced susceptibility to LUM (P = 0.035). The horizontal lines indicate the median drug IC50s.

Mentions: The MSPDBL1 haplotypes (n = 36) showed an association with CQ (P < 0.01) and LUM (P = 0.05) drug activity, while the haplotypes of MSPDBL2 (n = 31) showed an association with LUM (P = 0.03) (Table 1). Twelve Pfmspdbl1 SNPs (Table 2; see also Table S2 in the supplemental material) and 4 SNPs of Pfmspdbl2 (Table 3; see also Table S3 in the supplemental material) were associated with both CQ and LUM. Notably, Pfmspdbl2 SNP1783 (n = 31) codes for codon 591 (since the SNP followed 3 indels, 12 bp long), of which parasites containing serine were associated with reduced susceptibility to LUM (IC50, 97.6 nM; 95% CI, 77.7 to 199.8 nM; P = 0.04) (Fig. 2; Table 3). Codon 591S was also found at a high frequency (68%) in our population, similar to findings in Senegal (80% frequency) (10). This association of Pfmspdbl2 codon 591S with reduced susceptibility to LUM in a different African population adds support to the findings of the study in Senegal and suggests that codon 591 may be a marker for the surveillance of LUM resistance. Importantly, though, codon 591 is not likely to be the causal variant conferring resistance to LUM. Van Tyne et al. (10) demonstrated that stable integrants containing PfMSPDBL2 C591 were more sensitive to mefloquine, halofantrine, and LUM than those with the 591S parasite. The extensive use of LUM in Africa may be the major driving force favoring the high frequency of the 591S mutation.


The MSPDBL2 codon 591 polymorphism is associated with lumefantrine in vitro drug responses in Plasmodium falciparum isolates from Kilifi, Kenya.

Ochola-Oyier LI, Okombo J, Mwai L, Kiara SM, Pole L, Tetteh KK, Nzila A, Marsh K - Antimicrob. Agents Chemother. (2014)

Pfmspdbl2 codon 591 (n = 46) S allele is associated with reduced susceptibility to LUM (P = 0.035). The horizontal lines indicate the median drug IC50s.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325780&req=5

Figure 2: Pfmspdbl2 codon 591 (n = 46) S allele is associated with reduced susceptibility to LUM (P = 0.035). The horizontal lines indicate the median drug IC50s.
Mentions: The MSPDBL1 haplotypes (n = 36) showed an association with CQ (P < 0.01) and LUM (P = 0.05) drug activity, while the haplotypes of MSPDBL2 (n = 31) showed an association with LUM (P = 0.03) (Table 1). Twelve Pfmspdbl1 SNPs (Table 2; see also Table S2 in the supplemental material) and 4 SNPs of Pfmspdbl2 (Table 3; see also Table S3 in the supplemental material) were associated with both CQ and LUM. Notably, Pfmspdbl2 SNP1783 (n = 31) codes for codon 591 (since the SNP followed 3 indels, 12 bp long), of which parasites containing serine were associated with reduced susceptibility to LUM (IC50, 97.6 nM; 95% CI, 77.7 to 199.8 nM; P = 0.04) (Fig. 2; Table 3). Codon 591S was also found at a high frequency (68%) in our population, similar to findings in Senegal (80% frequency) (10). This association of Pfmspdbl2 codon 591S with reduced susceptibility to LUM in a different African population adds support to the findings of the study in Senegal and suggests that codon 591 may be a marker for the surveillance of LUM resistance. Importantly, though, codon 591 is not likely to be the causal variant conferring resistance to LUM. Van Tyne et al. (10) demonstrated that stable integrants containing PfMSPDBL2 C591 were more sensitive to mefloquine, halofantrine, and LUM than those with the 591S parasite. The extensive use of LUM in Africa may be the major driving force favoring the high frequency of the 591S mutation.

Bottom Line: The mechanisms of drug resistance development in the Plasmodium falciparum parasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear.We assessed the polymorphisms of Pfmspdbl2 for associations with LUM activity in a Kenyan population.MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P = 0.04).

View Article: PubMed Central - PubMed

Affiliation: Kenya Medical Research Institute/Wellcome Trust Collaborative Research Program, Kilifi, Kenya liochola@kemri-wellcome.org.

Show MeSH