Evidence for selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium falciparum by chloroquine and amodiaquine.
The 4-aminoquinolines chloroquine (CQ) and amodiaquine (AM) were used to treat Gambian children with uncomplicated falciparum malaria in a randomized drug trial. Blood samples were taken immediately before treatment (day 0), and at day 7 and day 28 after treatment. Samples from those parasitologically positive at day 7 following treatment ('early positives') and those positive at day 28 but negative at day 7 ('late positives') have been studied by PCR followed by restriction enzyme digestion to determine the allelic status of the pfmdr 1 locus at the codon-86 position (asparagine or tyrosine), previously associated with resistance to CQ. A significantly higher prevalence of the tyr-86 allele was observed in samples taken immediately before treatment (day 0) in the early positives group when compared with the late positives group. This suggests the tyr-86 allele contributes to drug resistance in the early positives group. This association remained significant for both CQ and AM groups, implying a common genetic basis of resistance. Predominance of the allele at day 7 is consistent with a strong selection in the first week following treatment. In the late positives group, a significantly higher prevalence of the tyr-86 allele was observed in the samples at day 28 when compared with those at day 0, suggestive of selection during the period day 7 to day 28. Differences were observed in the extent of this selection in the CQ and AM groups. The samples were genotyped at 3 unlinked polymorphic loci. These analyses suggested that most parasites observed at day 7 were probably recrudescences whereas most of those at day 28 were reinfections.
Duraisingh
M T
MT
Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, UK. m.duraisingh@lshtm.ac.uk
Drakeley
C J
CJ
Muller
O
O
Bailey
R
R
Snounou
G
G
Targett
G A
GA
Greenwood
B M
BM
Warhurst
D C
DC
D018528:ATP-Binding Cassette Transporters; D000483:Alleles; D000655:Amodiaquine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D003062:Codon; D004351:Drug Resistance; D017125:Genes, Protozoan; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D012641:Selection, Genetic; D014443:Tyrosine / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D003062:Codon; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D000655:Amodiaquine; D014443:Tyrosine; D002738:Chloroquine