title: Point mutations in the pfcrt and pfmdr-1 genes of Plasmodium falciparum and clinical response to chloroquine, among malaria patients from Nigeria.
abstract: Chloroquine (CQ) resistance in Plasmodium falciparum has been associated with specific point mutations in the pfcrt and pfmdr-1 genes. In the present study, 30 children aged 1-12 years, who were all suffering from acute, uncomplicated, P. falciparum malaria in Ibadan, Nigeria, were evaluated to assess the association between these mutations and clinical outcome following treatment with CQ. The parasites, in blood samples collected pre-treatment and, in those who failed treatment, on the day symptoms re-occurred post-treatment, were genotyped using the polymorphic MSP1, MSP2 and GLURP loci and PCR-RFLP. The results showed that, pre-treatment, all 30 patients had polyclonal infections, the mean numbers of P. falciparum clones detected per infection being 2.6 with MSP1, 4.2 with MSP2 and 2.8 with GLURP. The T76 allele of pfcrt and the Y86 allele of pfmdr-1 were found in 53% and 40%, respectively, of the pre-treatment samples from the 15 patients who failed CQ treatment, but the Y1246 mutation in pfmdr-1 was never detected. Although the parasites from the two patients with high-grade (RIII) resistance to CQ had both of these point mutations, the presence of the T76 allele of pfcrt or the Y86 allele of pfmdr-1 (considered individually) could not be used to predict treatment outcome. However, a high frequency of clonal multiplicity may confound attempts to associate the point mutations in pfcrt or pfmdr-1 with clinical response to CQ. It remains unclear whether the present results represent the characteristics of the predominant parasite populations in the study area. Further studies are needed before the strength of the association between the point mutations identified as markers of drug resistance and clinical outcome can be accurately evaluated, in this and other regions of intense transmission.
authors.affiliation: Malaria Research Laboratories, Postgraduate Institute for Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria.
authors.forename: T C
authors.initials: TC
authors.lastname: Happi
authors.forename: S M
authors.initials: SM
authors.lastname: Thomas
authors.forename: G O
authors.initials: GO
authors.lastname: Gbotosho
authors.forename: C O
authors.initials: CO
authors.lastname: Falade
authors.forename: D O
authors.initials: DO
authors.lastname: Akinboye
authors.forename: L
authors.initials: L
authors.lastname: Gerena
authors.forename: T
authors.initials: T
authors.lastname: Hudson
authors.forename: A
authors.initials: A
authors.lastname: Sowunmi
authors.forename: D E
authors.initials: DE
authors.lastname: Kyle
authors.forename: W
authors.initials: W
authors.lastname: Milhous
authors.forename: D F
authors.initials: DF
authors.lastname: Wirth
authors.forename: A M J
authors.initials: AM
authors.lastname: Oduola
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000208:Acute Disease; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use*; D004351:Drug Resistance / Q000502:physiology; D019353:Endemic Diseases / Q000517:prevention & control*; D017125:Genes, Protozoan / Q000235:genetics; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000469:parasitology; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009154:Mutation / Q000235:genetics; D009549:Nigeria / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine