title: In vitro sensitivity of Plasmodium falciparum clinical isolates from the China-Myanmar border area to quinine and association with polymorphism in the Na+/H+ exchanger.
abstract: Quinine resistance (QNR) in Plasmodium falciparum has been detected in many regions of the world where malaria is endemic. Genetic polymorphisms in at least four genes are implicated in QN susceptibility, and their significance often depends on the genetic background of the parasites. In this study, we have culture-adapted 60 P. falciparum clinical isolates from the China-Myanmar border and assessed their in vitro responses to QN. Our results showed that >50% of the parasite isolates displayed reduced sensitivity to QN, with a half-maximal inhibitory concentration (IC(50)) above 500 nM. Genotyping of pfcrt found that an overwhelming proportion of the parasite population had the chloroquine-resistant genotype, whereas pfmdr1 mutation genotypes and gene amplification were rare. Genotyping of the P. falciparum Na(+)/H(+) exchanger gene (pfnhe1) at the minisatellite ms4760 locus identified 10 haplotypes. Haplotype 7, which harbors three copies of the DNNND repeat, was the most predominant, accounting for nearly half of the parasite isolates. Correlation studies did not reveal significant associations of the polymorphisms in pfcrt and pfmdr1 genes with QN response. However, the ms4760 haplotypes were highly associated with in vitro QN responses. In particular, parasite isolates with an increased DNNND copy number tended to have significantly reduced QN susceptibility, whereas parasite isolates with a higher NHNDNHNNDDD copy number had increased QN susceptibility. This study provided further support for the importance of pfnhe1 polymorphisms in influencing QNR in P. falciparum.
authors.affiliation: Parasitology Department, School of Pharmaceutical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, Yunnan Province 650500, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Meng
authors.forename: Rongping
authors.initials: R
authors.lastname: Zhang
authors.forename: Henglin
authors.initials: H
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Fan
authors.forename: Xinzhuan
authors.initials: X
authors.lastname: Su
authors.forename: Jun
authors.initials: J
authors.lastname: Miao
authors.forename: Liwang
authors.initials: L
authors.lastname: Cui
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D002681:China; D026901:Membrane Transport Proteins / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D011803:Quinine / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011803:Quinine; D017923:Sodium-Hydrogen Exchangers; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum