title: Independent origin of plasmodium falciparum antifolate super-resistance, Uganda, Tanzania, and Ethiopia.
abstract: Super-resistant Plasmodium falciparum threatens the effectiveness of sulfadoxine-pyrimethamine in intermittent preventive treatment for malaria during pregnancy. It is characterized by the A581G Pfdhps mutation on a background of the double-mutant Pfdhps and the triple-mutant Pfdhfr. Using samples collected during 2004-2008, we investigated the evolutionary origin of the A581G mutation by characterizing microsatellite diversity flanking Pfdhps triple-mutant (437G+540E+581G) alleles from 3 locations in eastern Africa and comparing it with double-mutant (437G+540E) alleles from the same area. In Ethiopia, both alleles derived from 1 lineage that was distinct from those in Uganda and Tanzania. Uganda and Tanzania triple mutants derived from the previously characterized southeastern Africa double-mutant lineage. The A581G mutation has occurred multiple times on local Pfdhps double-mutant backgrounds; however, a novel microsatellite allele incorporated into the Tanzania lineage since 2004 illustrates the local expansion of emergent triple-mutant lineages.
authors: Michael
authors: M
authors: Alifrangis
authors: Sidsel
authors: S
authors: Nag
authors: Mette L
authors: ML
authors: Schousboe
authors: Deus
authors: D
authors: Ishengoma
authors: John
authors: J
authors: Lusingu
authors: Hirva
authors: H
authors: Pota
authors: Reginald A
authors: RA
authors: Kavishe
authors: Richard
authors: R
authors: Pearce
authors: Rosalynn
authors: R
authors: Ord
authors: Caroline
authors: C
authors: Lynch
authors: Seyoum
authors: S
authors: Dejene
authors: Jonathan
authors: J
authors: Cox
authors: John
authors: J
authors: Rwakimari
authors: Daniel T R
authors: DT
authors: Minja
authors: Martha M
authors: MM
authors: Lemnge
authors: Cally
authors: C
authors: Roper
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005002:Ethiopia / Q000453:epidemiology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000469:parasitology*; D018895:Microsatellite Repeats; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D013636:Tanzania / Q000453:epidemiology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014454:Uganda / Q000453:epidemiology; D055815:Young Adult
chemical_list: D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase
keywords: 581; Dihydrofolate reductase; Ethiopia; Pfdhfr; Pfdhps; Plasmodium falciparum; Tanzania; Uganda; dihydropteroate synthetase; eastern Africa; intermittent preventive treatment in pregnant women; malaria; microsatellite; parasites; resistance; single-nucleotide polymorphism; sulfadoxine-pyrimethamine; vector-borne infections