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Cited by 124Malaria Research and ControlPharmacogenetics and Drug MetabolismAntibiotic Resistance in Bacteria

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Anti-folate drug resistance in Africa: meta-analysis of reported dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant genotype frequencies in African Plasmodium falciparum parasite populations

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Sridaran, Sankar, McClintock, Shannon K, Syphard, Luke M, Herman, Karen M, Barnwell, John W, Udhayakumar, Venkatachalam·2010·Malaria Journal
DOI 10.1186/1475-2875-9-247PMC PMC2940896
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Abstract

BACKGROUND: Mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes of Plasmodium falciparum are associated with resistance to anti-folate drugs, most notably sulphadoxine-pyrimethamine (SP). Molecular studies document the prevalence of these mutations in parasite populations across the African continent. However, there is no systematic review examining the collective epidemiological significance of these studies. This meta-analysis attempts to: 1) summarize genotype frequency data that are critical for molecular surveillance of anti-folate resistance and 2) identify the specific challenges facing the development of future molecular databases. METHODS: This review consists of 220 studies published prior to 2009 that report the frequency of select dhfr and dhps mutations in 31 African countries. Maps were created to summarize the location and prevalence of the highly resistant dhfr triple mutant (N51I, C59R, S108N) genotype and dhps double mutant (A437G and K540E) genotype in Africa. A hierarchical mixed effects logistic regression was used to examine the influence of various factors on reported mutant genotype frequency. These factors include: year and location of study, age and clinical status of sampled population, and reporting conventions for mixed genotype data. RESULTS: A database consisting of dhfr and dhps mutant genotype frequencies from all African studies that met selection criteria was created for this analysis. The map illustrates particularly high prevalence of both the dhfr triple and dhps double mutant genotypes along the Kenya-Tanzania border and Malawi. The regression model shows a statistically significant increase in the prevalence of both the dhfr triple and dhps double mutant genotypes in Africa. CONCLUSION: Increasing prevalence of the dhfr triple mutant and dhps double mutant genotypes in Africa are consistent with the loss of efficacy of SP for treatment of clinical malaria in most parts of this continent. Continued assessment of the effectiveness of SP for the treatment of clinical malaria and intermittent preventive treatment in pregnancy is needed. The creation of a centralized resistance data network, such as the one proposed by the WorldWide Antimalarial Resistance Network (WWARN), will become a valuable resource for planning timely actions to combat drug resistant malaria.

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Figure 1 Snapshot of prevalence - dhfr triple mutant genotype (N51I, C59R, S108N).
Figure 1 Snapshot of prevalence - dhfr triple mutant genotype (N51I, C59R, S108N).CC BY · PubMed Central
Figure 2 Snapshot of prevalence - dhps double mutant genotype (A437G, K540E).
Figure 2 Snapshot of prevalence - dhps double mutant genotype (A437G, K540E).CC BY · PubMed Central
Figure 3 Time plot of reported frequency - dhfr triple mutant genotype (N51I, C59R, S108N).
Figure 3 Time plot of reported frequency - dhfr triple mutant genotype (N51I, C59R, S108N).CC BY · PubMed Central
Figure 4 Time plot of reported frequency - dhps double mutant genotype (A437G, K540E).
Figure 4 Time plot of reported frequency - dhps double mutant genotype (A437G, K540E).CC BY · PubMed Central
Figure 5 Country and study level random effects - dhfr triple mutant genotype (N51I, C59R, S108N).
Figure 5 Country and study level random effects - dhfr triple mutant genotype (N51I, C59R, S108N).CC BY · PubMed Central
Figure 6 Study level random effect - dhps double mutant genotype (A437G, K540E).
Figure 6 Study level random effect - dhps double mutant genotype (A437G, K540E).CC BY · PubMed Central

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Metadata

Authors
Sridaran, S., McClintock, S. K., Syphard, L. M., Herman, K. M., Barnwell, J. W., & Udhayakumar, V.
Affiliations
Centers for Disease Control and Prevention (US)
Corresponding author
Udhayakumar, Venkatachalam
ORCID
Udhayakumar, Venkatachalam
Venue
Malaria Journal
Publisher
Springer Science and Business Media LLC
Published
2010-08-30
Volume
9
Issue
1
Pages
247-247
ISSN
1475-2875 (ISSN-L)
DOI
10.1186/1475-2875-9-247
PMC
PMC2940896
OpenAlex
W2165336268
Cited by
124
References
106
Citations by year
2026: 5 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 8 · 2016: 11 · 2015: 10 · 2014: 8 · 2013: 15 · 2012: 18
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Malaria Journal (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Association of Public Health Laboratories
  • Centers for Disease Control and Prevention
  • Agency for Toxic Substances and Disease Registry
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
Keywords
Plasmodium falciparum, dihydrofolate reductase, dihydropteroate synthase, sulfadoxine-pyrimethamine, molecular surveillance, intermittent preventive treatment in pregnancy, Africa
MeSH terms
Africa, Antimalarials, Dihydropteroate Synthase, Drug Combinations, Drug Resistance, Gene Frequency, Genotype, Humans, Plasmodium falciparum, Pyrimethamine, Sulfadoxine, Tetrahydrofolate Dehydrogenase, Protozoan Proteins, DNA, Protozoan, Amino Acid Substitution, Mutation, Missense, Mutant Proteins

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