title: Two mutations in dihydrofolate reductase combined with one in the dihydropteroate synthase gene predict sulphadoxine-pyrimethamine parasitological failure in Ugandan children with uncomplicated falciparum malaria.
abstract: The point mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) and the dihydropteroate synthase (dhps) genes that are linked to sulphadoxine-pyrimethamine (SP) resistance in vitro have been well characterised. To determine whether a few of these mutations could predict SP treatment failure in vivo, two mutations (Asn-108 and Arg-59) in the dhfr gene and one (Glu-540) in the dhps gene were analysed according to the risk of SP parasitological failure (RI-RIII) at day 28 in pre-treatment isolates in 79 Ugandan children aged 6-59 (mean = 18.4, S.D. = 8.8) months with uncomplicated falciparum malaria. Neither the dhfr-108 (P = 0.3) nor the dhps-540 (P = 0.6) or dhfr-108 + dhps-540 (P = 0.04) mutations were significantly associated with SP parasitological failure. However, the dhfr-108 + dhfr-59 (P = 0.04), the dhfr-59 + dhps-540 (P = 0.04) and the dhfr-108 + dhfr-59 + dhps-540 (P = 0.02) mutations significantly increased the risk for SP parasitological failure. Our findings confirm an earlier report that the dhfr-59 and the dhps-540 mutations could be useful genetic markers for rapid screening of populations at high risk of SP resistance.
authors.affiliation: Ministry of Health, Epidemiological Surveillance Division, P. O. Box 7272, Kampala, Uganda, Belgium. atalisuna@yahoo.com
authors.forename: Ambrose O
authors.initials: AO
authors.lastname: Talisuna
authors.forename: Anne
authors.initials: A
authors.lastname: Nalunkuma-Kazibwe
authors.forename: Peter
authors.initials: P
authors.lastname: Langi
authors.forename: Theonest K
authors.initials: TK
authors.lastname: Mutabingwa
authors.forename: William W
authors.initials: WW
authors.lastname: Watkins
authors.forename: Eric
authors.initials: E
authors.lastname: Van Marck
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Egwang
authors.forename: Umberto
authors.initials: U
authors.lastname: D'Alessandro
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects* / Q000627:therapeutic use; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics*; D017354:Point Mutation; D011739:Pyrimethamine / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D013413:Sulfadoxine / Q000009:adverse effects* / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D013997:Time Factors; D017211:Treatment Failure; D014454:Uganda / Q000453:epidemiology
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine