title: Independent evolution of pyrimethamine resistance in Plasmodium falciparum isolates in Melanesia.
abstract: Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CNRNI [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (CIRNI) or quadruple (CIRNL) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.
authors.affiliation: Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University School of Medicine, 9-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. hiro-tm@research.twmu.ac.jp
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Mita
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Hideaki
authors.initials: H
authors.lastname: Eto
authors.forename: Lek
authors.initials: L
authors.lastname: Dysoley
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohmae
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.forename: Srivicha
authors.initials: S
authors.lastname: Krudsood
authors.forename: Sornchai
authors.initials: S
authors.lastname: Looareesuwan
authors.forename: Akira
authors.initials: A
authors.lastname: Kaneko
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kobayakawa
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D005075:Biological Evolution; D003430:Cross-Sectional Studies; D016054:DNA, Protozoan / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D017125:Genes, Protozoan; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D008542:Melanesia; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine