title: The role of Pfmdr1 and Pfcrt in changing chloroquine, amodiaquine, mefloquine and lumefantrine susceptibility in western-Kenya P. falciparum samples during 2008-2011.
abstract: Single Nucleotide Polymorphisms (SNPs) in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ) as well as amodiaquine (AQ) resistance. mefloquine (MQ) and lumefantrine (LU) sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008-2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild-type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001). Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001) during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART) Combination Therapy (ACT) administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future.
authors.affiliation: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System-DEID-GEIS Program, United States Army Medical Research Unit-Kenya-USAMRU-K, Nairobi, Kenya. fredrickeyase@yahoo.com
authors.forename: Fredrick L
authors.initials: FL
authors.lastname: Eyase
authors.forename: Hoseah M
authors.initials: HM
authors.lastname: Akala
authors.forename: Luiser
authors.initials: L
authors.lastname: Ingasia
authors.forename: Agnes
authors.initials: A
authors.lastname: Cheruiyot
authors.forename: Angela
authors.initials: A
authors.lastname: Omondi
authors.forename: Charles
authors.initials: C
authors.lastname: Okudo
authors.forename: Dennis
authors.initials: D
authors.lastname: Juma
authors.forename: Redemptah
authors.initials: R
authors.lastname: Yeda
authors.forename: Ben
authors.initials: B
authors.lastname: Andagalu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wanja
authors.forename: Edwin
authors.initials: E
authors.lastname: Kamau
authors.forename: David
authors.initials: D
authors.lastname: Schnabel
authors.forename: Wallace
authors.initials: W
authors.lastname: Bulimo
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Walsh
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D000655:Amodiaquine / Q000627:therapeutic use; D000962:Antimalarials / Q000627:therapeutic use*; D002738:Chloroquine / Q000627:therapeutic use; D016054:DNA, Protozoan / Q000235:genetics; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D004983:Ethanolamines / Q000627:therapeutic use; D005449:Fluorenes / Q000627:therapeutic use; D006239:Haplotypes; D006801:Humans; D020128:Inhibitory Concentration 50; D007630:Kenya; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D015767:Mefloquine / Q000627:therapeutic use; D026901:Membrane Transport Proteins / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D000655:Amodiaquine; D000962:Antimalarials; D002738:Chloroquine; D016054:DNA, Protozoan; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D015767:Mefloquine; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum