The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin

Although chloroquine-resistance (CQR) in Plasmodium falciparum is increasin g and resistance to other blood schizonticidal anti-malarials has been repo rted, the molecular basis remains unclear. In this study fresh field isolat es were obtained from The Gambia, an area of emerging CQR and tested for se nsitivity to the anti-malarial drugs mefloquine, halofantrine, artemisinin, dihydroartemisinin, chloroquine and quinine. Sequence polymorphisms in the pfmdr 1 gene and size polymorphisms in the cg2 gene were assessed using PC R-based systems. A strong association was observed between the presence of the tyr-86 allele of pfmdr 1 and increased sensitivity to mefloquine and ha lofantrine. as well as the structurally unrelated drugs artemisinin and dih ydroartemisinin. A weaker association was found between the presence of tyr -86 and increased resistance to chloroquine and quinine. The cg2 Dd2-like o mega repeal size polymorphism was associated with increased resistance to c hloroquine and increased sensitivity to mefloquine and halofantrine. An int ragenic association was also found between a polymorphism in the polyaspara gine linker region of pfmdr 1 and the tyr-86 allele, which may be due to ge netic hitchhiking, indicative of recent selection by chloroquine. Our data support a hypothesis where the pfmdr 1 gene confers a true multidrug resist ance phenotype which is lost by mutation. (C) 2000 Elsevier Science B.V. Al l rights reserved.