title: Selection of Plasmodium falciparum multidrug resistance gene 1 alleles in asexual stages and gametocytes by artemether-lumefantrine in Nigerian children with uncomplicated falciparum malaria.
abstract: We assessed Plasmodium falciparum mdr1 (Pfmdr1) gene polymorphisms and copy numbers as well as P. falciparum Ca(2+) ATPase (PfATPase6) gene polymorphisms in 90 Nigerian children presenting with uncomplicated falciparum malaria and enrolled in a study of the efficacy of artemether-lumefantrine (AL). The nested PCR-restriction fragment length polymorphism and the quantitative real-time PCR methodologies were used to determine the alleles of the Pfmdr1 and PfATPase6 genes and the Pfmdr1 copy number variation, respectively, in patients samples collected prior to treatment and at the reoccurrence of parasites during a 42-day follow-up. The Pfmdr1 haplotype 86N-184F-1246D was significantly associated (P < 0.00001) with treatment failures and was selected for among posttreatment samples obtained from patients with newly acquired or recrudescing infections (P < 0.00001; chi(2) = 36.5) and in gametocytes (log rank statistic = 5; P = 0.0253) after treatment with AL. All pre- and posttreatment samples as well as gametocytes harbored a single copy of the Pfmdr1 gene and the wild-type allele (L89) at codon 89 of the PfATPase6 gene. These findings suggest that polymorphisms in the Pfmdr1 gene are under AL selection pressure. Pfmdr1 polymorphisms may result in reduction in the therapeutic efficacy of this newly adopted combination treatment for uncomplicated falciparum malaria in Saharan countries of Africa.
authors.affiliation: Malaria Research Laboratories, IMRAT, College of Medicine, University of Ibadan, Ibadan, Nigeria. chappi@hsph.harvard.edu
authors.forename: C T
authors.initials: CT
authors.lastname: Happi
authors.forename: G O
authors.initials: GO
authors.lastname: Gbotosho
authors.forename: O A
authors.initials: OA
authors.lastname: Folarin
authors.forename: A
authors.initials: A
authors.lastname: Sowunmi
authors.forename: T
authors.initials: T
authors.lastname: Hudson
authors.forename: M
authors.initials: M
authors.lastname: O'Neil
authors.forename: W
authors.initials: W
authors.lastname: Milhous
authors.forename: D F
authors.initials: DF
authors.lastname: Wirth
authors.forename: A M J
authors.initials: AM
authors.lastname: Oduola
mesh_terms: D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D004983:Ethanolamines; D005449:Fluorenes / Q000627:therapeutic use*; D005500:Follow-Up Studies; D018628:Gene Dosage; D019450:Genes, MDR; D006239:Haplotypes; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology*; D009549:Nigeria / Q000453:epidemiology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes