EVIDENCE FOR SELECTION FOR THE TYROSINE-86 ALLELE OF THE PFMDR-1 GENEOF 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 r andomized drug trial. Blood samples were taken immediately before trea tment (day 0), and at day 7 and day 28 after treatment. Samples from t hose 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 di gestion to determine the allelic status of the pfmdr 1 locus at the co don-86 position (asparagine or tyrosine), previously associated with r esistance to CQ. A significantly higher prevalence of the tyr-86 allel e was observed in samples taken immediately before treatment (day 0) i n the early positives group when compared with the late positives grou p. This suggests the tyr-86 allele contributes to drug resistance in t he early positives group. This association remained significant for bo th CQ and AM groups, implying a common genetic basis of resistance. Pr edominance of the allele at day 7 is consistent with a strong selectio n 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 o f selection during the period day 7 to day 28. Differences were observ ed in the extent of this selection in the CQ and AM groups. The sample s were genotyped at 3 unlinked polymorphic loci. These analyses sugges ted that most parasites observed at day 7 were probably recrudescences whereas most of those at day 28 were reinfections.