TY - JOUR
T1 - Antifolate resistance in Plasmodium falciparum
T2 - Multiple origins and identification of novel dhfr alleles
AU - McCollum, Andrea M.
AU - Poe, Amanda C.
AU - Hamel, Mary
AU - Huber, Curtis
AU - Zhou, Zhiyong
AU - Shi, Ya Ping
AU - Ouma, Peter
AU - Vulule, John
AU - Bloland, Peter
AU - Slutsker, Laurence
AU - Barnwell, John W.
AU - Udhayakumar, Venkatachalam
AU - Escalante, Ananias A.
N1 - Funding Information:
Financial support: Opportunistic Infections Working Group, Centers for Disease Control and Prevention and the Antimicrobial Resistance Working Group, Centers for Disease Control and Prevention; National Institutes of Health (grant R01 GM60740 to A.A.E.).
Funding Information:
We thank the Atlanta Research and Education Foundation, Atlanta VA Medical Center, for supporting this work. We thank the director of the Kenya Medical Research Institute for supporting this work and approving the publication of this article. We are grateful to Christopher Plowe for discussion and comments that improved this article. We also thank the reviewers for comments that improved this article.
PY - 2006/7/15
Y1 - 2006/7/15
N2 - Background. Sulfadoxine-pyrimethamine has been widely used as first-line therapy for uncomplicated malaria throughout sub-Saharan Africa. Recent studies conducted in Asia and Africa suggest the triple-mutant dhfr genotype (51I/59R/108N) may have been generated as a single event in Southeast Asia, with subsequent spread of the single lineage to the African continent, but this hypothesis needs further validation. Methods. Direct sequencing of polymerase chain reaction (PCR) products, pyrosequencing, and cloning of PCR products were utilized to identify mutations in dhfr. To investigate the evolutionary history of dhfr alleles, we assayed microsatellite loci flanking dhfr along chromosome 4. Results. A total of 15 of 479 samples from western Kenya showed the presence of I164L, in 5 different genotypes. We document C50R in 2 of our samples. Using microsatellite markers, we show 2 haplotypes for both the 51I/ 108N/164L and 51I/59R/108N/164L genotypes. Our results also show multiple lineages for the triple-mutant dhfr genotype in Africa. Conclusions. These findings highlight the importance of local characterization of alleles before molecular surveillance of drug-resistant alleles is considered in different endemic settings and populations.
AB - Background. Sulfadoxine-pyrimethamine has been widely used as first-line therapy for uncomplicated malaria throughout sub-Saharan Africa. Recent studies conducted in Asia and Africa suggest the triple-mutant dhfr genotype (51I/59R/108N) may have been generated as a single event in Southeast Asia, with subsequent spread of the single lineage to the African continent, but this hypothesis needs further validation. Methods. Direct sequencing of polymerase chain reaction (PCR) products, pyrosequencing, and cloning of PCR products were utilized to identify mutations in dhfr. To investigate the evolutionary history of dhfr alleles, we assayed microsatellite loci flanking dhfr along chromosome 4. Results. A total of 15 of 479 samples from western Kenya showed the presence of I164L, in 5 different genotypes. We document C50R in 2 of our samples. Using microsatellite markers, we show 2 haplotypes for both the 51I/ 108N/164L and 51I/59R/108N/164L genotypes. Our results also show multiple lineages for the triple-mutant dhfr genotype in Africa. Conclusions. These findings highlight the importance of local characterization of alleles before molecular surveillance of drug-resistant alleles is considered in different endemic settings and populations.
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U2 - 10.1086/504687
DO - 10.1086/504687
M3 - Article
C2 - 16779725
AN - SCOPUS:33746125737
SN - 0022-1899
VL - 194
SP - 189
EP - 197
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 2
ER -