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Population-based validation of dihydrofolate reductase gene mutations for the prediction of sulfadoxine-pyrimethamine resistance in Uganda

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dc.contributor.author Talisuna, A. O. en_US
dc.contributor.author Langi, P. en_US
dc.contributor.author Mutabingwa, T. K. en_US
dc.contributor.author Watkins, W. en_US
dc.contributor.author Van Marck, E. en_US
dc.contributor.author Egwang, T. G. en_US
dc.contributor.author D'Alessandro, U. en_US
dc.date.accessioned 2007-12-06T14:34:12Z
dc.date.available 2007-12-06T14:34:12Z
dc.date.issued 2003 en_US
dc.identifier.issn 0035-9203 en_US
dc.identifier.doi http://dx.doi.org/10.1016/S0035-9203(03)90163-5
dc.identifier.other ITG-P1B en_US
dc.identifier.other ITG-PLA en_US
dc.identifier.other PARAS en_US
dc.identifier.other U-MALAR en_US
dc.identifier.other JIF en_US
dc.identifier.other DOI en_US
dc.identifier.other ABSTRACT en_US
dc.identifier.uri http://hdl.handle.net/10390/289
dc.description.abstract Mutations in the dihydrofolate reductase gene (dhfr) of Plasmodium falciparum have been proposed as molecular markers for the surveillance of sulfadoxine-pyrimethamine (SP)-resistant malaria, but such proposals have not been validated. At 7 Ugandan sites in 1999, we determined the population-based prevalence of infections with mutations and the mutant allele frequency of dhfr codons 108, 51, and 59 using a random sample of infected individuals aged 1-45 years. Sulfadoxine-pyrimethamine treatment failure was independently estimated by in vivo tests in 327 children aged 6-59 months with clinical malaria. The prevalence of infections with the single point mutations and the dhfr codons 108 and 51 mutant allele frequency were not correlated to SP treatment failure. However, the dhfr codon 59 mutant allele frequency was positively correlated to SP treatment failure (r = 0.72, P = 0.06). The ratio of the infections with the mutant to wild genotype (M/W) and that of the mutant to wild allele (MA/WA) had the same values. Both dhfr codon 59 M/W and MA/WA ratio were significantly and positively correlated to SP treatment failure (r = 0.73, P = 0.05). Moreover, the prevalence of infections with only 2 mutations (Asn-108 plus Ile-51) was significantly and inversely correlated to the prevalence of infections with 3 mutations (Asn-108 plus Ile-51 plus Arg-59) (r = 0.92, P = 0.004), suggesting the stepwise accumulation of the dhfr mutations is Asn-108 Ile-51 Arg-59 and further supporting the idea of using the dhfr codon 59 M/W ratio as a molecular index for the prediction of SP treatment failure. Atthe population level, the dhfr codon 59 M/W ratio is a simple and stable index for the estimation of SP treatment failure. en_US
dc.language English en_US
dc.publisher Elsevier
dc.subject Protozoal diseases en_US
dc.subject Malaria en_US
dc.subject Plasmodium falciparum en_US
dc.subject Sulfadoxine-pyrimethamine en_US
dc.subject Drug resistance en_US
dc.subject Molecular markers en_US
dc.subject Dihydrofolate reductase gene en_US
dc.subject Mutations en_US
dc.subject Uganda en_US
dc.subject Africa, East en_US
dc.title Population-based validation of dihydrofolate reductase gene mutations for the prediction of sulfadoxine-pyrimethamine resistance in Uganda en_US
dc.type Article en_US
dc.citation.issue 3 en_US
dc.citation.jtitle Transactions of the Royal Society of Tropical Medicine and Hygiene en_US
dc.citation.volume 97 en_US
dc.citation.pages 338-342 en_US
dc.publisher.place Amsterdam
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/15228255
dc.identifier.url http://www.elsevier.com/locate/trstmh
dc.citation.jabbreviation Trans R Soc Trop Med Hyg en_US


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