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Monitoring of malaria parasite resistance to chloroquine and sulphadoxine-pyrimethamine in the Solomon Islands by DNA microarray technology.

Ballif M, Hii J, Marfurt J, Crameri A, Fafale A, Felger I, Beck HP, Genton B - Malar. J. (2010)

Bottom Line: The obtained results indicated the presence of a very homogenous P. falciparum population circulating in the community.Although CQ+SP could still clear most infections, seven fixed mutations associated with CQ resistance and two fixed mutations related to SP resistance were observed.Whether the absence of mutations in pfATPase6 indicates the efficacy of artemisinin derivatives remains to be proven.

View Article: PubMed Central - HTML - PubMed

Affiliation: Swiss Tropical and Public Health Institute, Department of Medical Parasitology and Biology of Infection, Department of Epidemiology and Public Health, Socinstrasse 57, 4002 Basel, Switzerland.

ABSTRACT

Background: Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI). The analysis of single nucleotide polymorphisms (SNPs) in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ) resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP) resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives.

Methods: The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection.

Results: The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39.

Conclusion: This work provides the first insight into drug resistance markers of P. falciparum in the SI. The obtained results indicated the presence of a very homogenous P. falciparum population circulating in the community. Although CQ+SP could still clear most infections, seven fixed mutations associated with CQ resistance and two fixed mutations related to SP resistance were observed. Whether the absence of mutations in pfATPase6 indicates the efficacy of artemisinin derivatives remains to be proven.

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Related in: MedlinePlus

Observed haplotypes of SNPs related to resistance to CQ, SP and artemisinin derivatives. A haplotype is defined by the combination of mutations in genes related to drug resistance. Grey indicates mutations and white indicates wild-type. Two different haplotypes were observed in genes pfmdr1 and pfcrt. One haplotype was observed in genes pfdhfr and pfdhps. One haplotype was observed in gene pfATPase6. n corresponds to the number of samples assessed for the analysis.
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Figure 2: Observed haplotypes of SNPs related to resistance to CQ, SP and artemisinin derivatives. A haplotype is defined by the combination of mutations in genes related to drug resistance. Grey indicates mutations and white indicates wild-type. Two different haplotypes were observed in genes pfmdr1 and pfcrt. One haplotype was observed in genes pfdhfr and pfdhps. One haplotype was observed in gene pfATPase6. n corresponds to the number of samples assessed for the analysis.

Mentions: Overall, the analysed population showed to be very homogenous (Figure 2). Two different haplotypes were observed for the two CQ resistance-associated genes. With 70% of the patients having a single infection and the unambiguous DNA microarray signals, it was considered that co-infecting clones had the same pattern of SNPs. The most dominant haplotype showed mutations at positions pfmdr1 N86Y and pfcrt C72 S, N75D/E, K76T, A220 S, N326 D, and I356L, and was observed in 98.4% (61/62) of the population. The second haplotype was observed in one sample only (1.6%) and differed from the first one by having one additional mutation at position N1042 D in pfmdr1. Other SNPs related to CQ resistance were all wild-type.


Monitoring of malaria parasite resistance to chloroquine and sulphadoxine-pyrimethamine in the Solomon Islands by DNA microarray technology.

Ballif M, Hii J, Marfurt J, Crameri A, Fafale A, Felger I, Beck HP, Genton B - Malar. J. (2010)

Observed haplotypes of SNPs related to resistance to CQ, SP and artemisinin derivatives. A haplotype is defined by the combination of mutations in genes related to drug resistance. Grey indicates mutations and white indicates wild-type. Two different haplotypes were observed in genes pfmdr1 and pfcrt. One haplotype was observed in genes pfdhfr and pfdhps. One haplotype was observed in gene pfATPase6. n corresponds to the number of samples assessed for the analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2959069&req=5

Figure 2: Observed haplotypes of SNPs related to resistance to CQ, SP and artemisinin derivatives. A haplotype is defined by the combination of mutations in genes related to drug resistance. Grey indicates mutations and white indicates wild-type. Two different haplotypes were observed in genes pfmdr1 and pfcrt. One haplotype was observed in genes pfdhfr and pfdhps. One haplotype was observed in gene pfATPase6. n corresponds to the number of samples assessed for the analysis.
Mentions: Overall, the analysed population showed to be very homogenous (Figure 2). Two different haplotypes were observed for the two CQ resistance-associated genes. With 70% of the patients having a single infection and the unambiguous DNA microarray signals, it was considered that co-infecting clones had the same pattern of SNPs. The most dominant haplotype showed mutations at positions pfmdr1 N86Y and pfcrt C72 S, N75D/E, K76T, A220 S, N326 D, and I356L, and was observed in 98.4% (61/62) of the population. The second haplotype was observed in one sample only (1.6%) and differed from the first one by having one additional mutation at position N1042 D in pfmdr1. Other SNPs related to CQ resistance were all wild-type.

Bottom Line: The obtained results indicated the presence of a very homogenous P. falciparum population circulating in the community.Although CQ+SP could still clear most infections, seven fixed mutations associated with CQ resistance and two fixed mutations related to SP resistance were observed.Whether the absence of mutations in pfATPase6 indicates the efficacy of artemisinin derivatives remains to be proven.

View Article: PubMed Central - HTML - PubMed

Affiliation: Swiss Tropical and Public Health Institute, Department of Medical Parasitology and Biology of Infection, Department of Epidemiology and Public Health, Socinstrasse 57, 4002 Basel, Switzerland.

ABSTRACT

Background: Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI). The analysis of single nucleotide polymorphisms (SNPs) in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ) resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP) resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives.

Methods: The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection.

Results: The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39.

Conclusion: This work provides the first insight into drug resistance markers of P. falciparum in the SI. The obtained results indicated the presence of a very homogenous P. falciparum population circulating in the community. Although CQ+SP could still clear most infections, seven fixed mutations associated with CQ resistance and two fixed mutations related to SP resistance were observed. Whether the absence of mutations in pfATPase6 indicates the efficacy of artemisinin derivatives remains to be proven.

Show MeSH
Related in: MedlinePlus