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Population-based validation of dihydrofolate reductase gene mutations for the prediction of sulfadoxine-pyrimethamine resistance in Uganda.
- Source :
-
Transactions of the Royal Society of Tropical Medicine and Hygiene [Trans R Soc Trop Med Hyg] 2003 May-Jun; Vol. 97 (3), pp. 338-42. - Publication Year :
- 2003
-
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.
- Subjects :
- Adolescent
Adult
Animals
Child
Child, Preschool
Drug Combinations
Drug Resistance genetics
Gene Frequency
Genes, Protozoan genetics
Genetic Markers
Humans
Infant
Malaria, Falciparum drug therapy
Malaria, Falciparum epidemiology
Malaria, Falciparum parasitology
Middle Aged
Plasmodium falciparum enzymology
Plasmodium falciparum genetics
Prevalence
Treatment Failure
Uganda epidemiology
Antimalarials pharmacology
Plasmodium falciparum drug effects
Point Mutation
Pyrimethamine pharmacology
Sulfadoxine pharmacology
Tetrahydrofolate Dehydrogenase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0035-9203
- Volume :
- 97
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Transactions of the Royal Society of Tropical Medicine and Hygiene
- Publication Type :
- Academic Journal
- Accession number :
- 15228255
- Full Text :
- https://doi.org/10.1016/s0035-9203(03)90163-5