Evidence for selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium falciparum by chloroquine and amodiaquine

Parasitology. 1997 Mar;114 ( Pt 3):205-11. doi: 10.1017/s0031182096008487.

Abstract

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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters*
  • Alleles
  • Amodiaquine / pharmacology*
  • Amodiaquine / therapeutic use
  • Animals
  • Antimalarials / pharmacology
  • Antimalarials / therapeutic use
  • Child
  • Child, Preschool
  • Chloroquine / pharmacology*
  • Chloroquine / therapeutic use
  • Codon
  • Drug Resistance
  • Genes, Protozoan
  • Humans
  • Infant
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / parasitology
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / genetics*
  • Protozoan Proteins / genetics*
  • Selection, Genetic
  • Tyrosine / genetics

Substances

  • ATP-Binding Cassette Transporters
  • Antimalarials
  • Codon
  • Protozoan Proteins
  • mdr gene protein, Plasmodium
  • Amodiaquine
  • Tyrosine
  • Chloroquine