title: Plasmodium falciparum multidrug resistance protein 1 (pfmrp1) gene and its association with in vitro drug susceptibility of parasite isolates from north-east Myanmar.
abstract: OBJECTIVE
  Plasmodium falciparum multidrug resistance protein 1 (pfmrp1) has recently emerged as an important determinant of drug resistance and mutations in the gene have been associated with several drugs. The aim of this study was to understand the level of genetic diversity in pfmrp1 and to determine the association of different mutations with altered drug susceptibilities of P. falciparum.
  
  
  METHODS
  We analysed 193 sequences of pfmrp1 from South-East Asia, west Asia, Africa, Oceania and South America. We measured the level of genetic diversity and determined signatures of selection on the gene. In vitro susceptibilities of 28 P. falciparum isolates from north-east Myanmar to a panel of seven commonly used antimalarials were determined. Statistical analysis was performed to determine the association of different mutations with in vitro drug susceptibilities.
  
  
  RESULTS
  A total of 28 single nucleotide polymorphisms were identified in 193 sequences, of which 22 were non-synonymous. Whereas mutations in the pfmrp1 gene were conserved among different countries within a continent, they were different between continents. Seven non-synonymous mutations were identified in the north-east Myanmar isolates; all were relatively frequent in this region as well as in other neighbouring countries. Molecular evolutionary analysis detected signatures of positive selection on the gene. Moreover, some mutations in this gene were found to be associated with reduced susceptibilities to chloroquine, mefloquine, pyronaridine and lumefantrine.
  
  
  CONCLUSIONS
  Evidence of the positive selection of pmfrp1 and its association with the susceptibilities of parasites to multiple drugs signifies its potential as an important candidate for monitoring drug resistance.
authors.affiliation: Department of Entomology, Pennsylvania State University, 501 ASI Building, University Park, PA 16802 USA.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Gupta
authors.affiliation: Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, Yunnan Province, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Entomology, Pennsylvania State University, 501 ASI Building, University Park, PA 16802 USA.
authors.forename: Zenglei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, Yunnan Province, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Entomology, Pennsylvania State University, 501 ASI Building, University Park, PA 16802 USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Miao
authors.affiliation: Department of Entomology, Pennsylvania State University, 501 ASI Building, University Park, PA 16802 USA luc2@psu.edu.
authors.forename: Liwang
authors.initials: L
authors.lastname: Cui
authors.affiliation: Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, Yunnan Province, China.
authors.forename: Zhaoqing
authors.initials: Z
authors.lastname: Yang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000962:Antimalarials / Q000494:pharmacology*; D001483:Base Sequence; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D004983:Ethanolamines / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D005843:Geography; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D015767:Mefloquine / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009154:Mutation; D002052:Myanmar; D009287:Naphthyridines / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D002738:Chloroquine; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009287:Naphthyridines; C027871:pyronaridine
keywords: ABC transporter; drug resistance; malaria parasite