title: Plasmodium falciparum pfcrt and pfmdr1 polymorphisms are associated with the pfdhfr N108 pyrimethamine-resistance mutation in isolates from Ghana.
abstract: The Plasmodium falciparum chloroquine resistance transporter gene (pfcrt) T76 and multidrug resistance gene analogue (pfmdr1) Y86 mutations are associated with chloroquine(CQ)-resistance. In isolates from 172 pregnant women living in the area of Agogo, Ghana, pfcrt T76 was detected in 69% and pfmdr1 Y86 in 66%. Pfcrt T76 but not pfmdr1 Y86 was more prevalent in samples from women with residual CQ in urine or serum. Parasite densities and multiplicity of infection of pfmdr wild type but not of resistant isolates were reduced by CQ. Adjusted for CQ and pyrimethamine (PYR) in urine, the P. falciparum dihydrofolate reductase (pfdhfr) N108 mutation which confers PYR-resistance was 3.1 and 3 times, respectively, more likely to be detected in isolates containing pfcrt and pfmdr1 mutations than in those comprising wild type alleles. Pfcrt, pfmdr, and pfdhfr mutations are frequent in P. falciparum from this part of Ghana which may limit the choice of drugs for the prevention of malaria in pregnancy. The association of CQ- and PYR-resistance mutations independent of recent drug use could indicate accelerated development of resistance to structurally unrelated drugs. Alternatively, it may reflect selection of resistance in persisting infections due to no longer detectable drug pressure.
authors.affiliation: Institut für Tropenmedizin, Medizinische Fakultät Charité, Humboldt Universität zu Berlin, Germany. frank.mockenhaupt@charite.de
authors.forename: F P
authors.initials: FP
authors.lastname: Mockenhaupt
authors.forename: T A
authors.initials: TA
authors.lastname: Eggelte
authors.forename: H
authors.initials: H
authors.lastname: Till
authors.forename: U
authors.initials: U
authors.lastname: Bienzle
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use / Q000652:urine; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use / Q000652:urine; D016054:DNA, Protozoan / Q000097:blood / Q000235:genetics; D004351:Drug Resistance; D005260:Female; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology* / Q000635:transmission; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000188:drug therapy / Q000453:epidemiology*; D015995:Prevalence; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use / Q000652:urine; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D016054:DNA, Protozoan; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine