title: Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.
abstract: Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ICVS/3B's, PT Government Associate Laboratory, Guimarães, Braga, Portugal Malaria Research Laboratory, Department of Medicine, Karolinska Institutet, Stockholm, Sweden mariaveiga@ecsaude.uminho.pt.
authors.forename: Maria Isabel
authors.identifier: http://orcid.org/0000-0002-2205-8102
authors.initials: MI
authors.lastname: Veiga
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ICVS/3B's, PT Government Associate Laboratory, Guimarães, Braga, Portugal.
authors.forename: Nuno S
authors.initials: NS
authors.lastname: Osório
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore Drug Resistance and Pharmacogenetics, Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Pedro Eduardo
authors.initials: PE
authors.lastname: Ferreira
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Franzén
authors.affiliation: Malaria Research Laboratory, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sabina
authors.initials: S
authors.lastname: Dahlstrom
authors.affiliation: Harpur College of Arts and Sciences, Binghamton University, The State University of New York, Binghamton, New York, USA.
authors.forename: J Koji
authors.initials: JK
authors.lastname: Lum
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Drug Resistance and Pharmacogenetics, Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal Harpur College of Arts and Sciences, Binghamton University, The State University of New York, Binghamton, New York, USA Division of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Gil
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D001692:Biological Transport; D002738:Chloroquine / Q000494:pharmacology; D002875:Chromosomes / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D054643:INDEL Mutation; D016778:Malaria, Falciparum / Q000469:parasitology; D015767:Mefloquine / Q000494:pharmacology; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011804:Quinolines / Q000494:pharmacology; D013785:Thailand; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D002738:Chloroquine; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines; C513499:Mdr2 protein, Plasmodium falciparum; C031327:artemisinin; C034759:piperaquine; D010879:Piperazines