title: Relationship between the Pfcrt T76 and the Pfmdr-1 Y86 mutations in Plasmodium falciparum and in vitro/in vivo chloroquine resistance in Burkina Faso, West Africa.
abstract: The relationship between Pfcrt T76 and Pfmdr-1 Y86 mutations in Plasmodium falciparum was explored in samples from patients with uncomplicated malaria and tested in vitro and in vivo with chloroquine (CQ) in Burkina Faso. The two mutations were strongly related. The Pfcrt T76 mutation was found in 82% of the samples having the Pfmdr-1 Y86 mutation too (odds ratio (OR)=4.8 [95% CI: 1.7-13.3]; P=0.002). However, only half (16/34) of samples with Pfcrt T76 mutation had also the Pfmdr-1 Y86 mutation. The latter was apparently associated with in vitro resistance (OR=4.8 [95% CI: 1.4-16.5]; P=0.01) but such association disappeared (P=0.77) after adjusting for the presence of the Pfcrt T76 mutation. This suggests that the occurrence of the Pfmdr-1 Y86 mutation is dependent on that of Pfcrt T76 mutation and could explain previous reports linking the Pfmdr-1 Y86 mutation with CQ resistance (CQR). The isolates carrying both the Pfcrt K76 and Pfmdr-1 N86 alleles (wild/wild (WW)) and the single mutant Pfmdr-1 Y86 (WM) had the lowest IC50 geometric mean (GMIC50) values, while those carrying both Pfcrt T76/Pfmdr-1 Y86 alleles (mutant/mutant (MM)), and the single mutant Pfcrt T76 (MW) had the highest. Among pre-treatment samples there was a strong linkage disequilibrium with an excess of MM and WW and a deficit of single mutants (MW and WM), suggesting that parasite fitness is higher for the former and lower for the latter.
authors.affiliation: Institut de Recherche en Sciences de la Santé, Bobo Dioulasso, Burkina Faso.
authors.forename: Halidou
authors.initials: H
authors.lastname: Tinto
authors.forename: Jean Bosco
authors.initials: JB
authors.lastname: Ouédraogo
authors.forename: Annette
authors.initials: A
authors.lastname: Erhart
authors.forename: Chantal
authors.initials: C
authors.lastname: Van Overmeir
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.forename: Eric
authors.initials: E
authors.lastname: Van Marck
authors.forename: Tinga Robert
authors.initials: TR
authors.lastname: Guiguemdé
authors.forename: Umberto
authors.initials: U
authors.lastname: D'Alessandro
mesh_terms: D000293:Adolescent; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002050:Burkina Faso; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology*; D004352:Drug Resistance, Microbial / Q000235:genetics; D005828:Genetics, Population; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics*; D026901:Membrane Transport Proteins; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine