title: Genomic Analysis Reveals a Common Breakpoint in Amplifications of the Plasmodium vivax Multidrug Resistance 1 Locus in Thailand.
abstract: In regions of coendemicity for Plasmodium falciparum and Plasmodium vivax where mefloquine is used to treat P. falciparum infection, drug pressure mediated by increased copy numbers of the multidrug resistance 1 gene (pvmdr1) may select for mefloquine-resistant P. vivax Surveillance is not undertaken routinely owing in part to methodological challenges in detection of gene amplification. Using genomic data on 88 P. vivax samples from western Thailand, we identified pvmdr1 amplification in 17 isolates, all exhibiting tandem copies of a 37.6-kilobase pair region with identical breakpoints. A novel breakpoint-specific polymerase chain reaction assay was designed to detect the amplification. The assay demonstrated high sensitivity, identifying amplifications in 13 additional, polyclonal infections. Application to 132 further samples identified the common breakpoint in all years tested (2003-2015), with a decline in prevalence after 2012 corresponding to local discontinuation of mefloquine regimens. Assessment of the structure of pvmdr1 amplification in other geographic regions will yield information about the population-specificity of the breakpoints and underlying amplification mechanisms.
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic Lerner Research institute, Ohio.
authors.forename: David
authors.initials: D
authors.lastname: Serre
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton Wellcome Trust Centre for Human Genetics.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Pearson
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton Wellcome Trust Centre for Human Genetics.
authors.forename: Roberto
authors.initials: R
authors.lastname: Amato
authors.affiliation: Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Tak.
authors.forename: Kanlaya
authors.initials: K
authors.lastname: Sriprawat
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Australia.
authors.forename: Sheren
authors.initials: S
authors.lastname: To
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Handayuni
authors.affiliation: Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
authors.forename: Rossarin
authors.initials: R
authors.lastname: Suwanarusk
authors.affiliation: Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Drury
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton.
authors.forename: Jim
authors.initials: J
authors.lastname: Stalker
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton Medical Research Council Centre for Genomics and Global Health Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Olivo
authors.initials: O
authors.lastname: Miotto
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton Wellcome Trust Centre for Human Genetics Medical Research Council Centre for Genomics and Global Health.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, United Kingdom Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Tak.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Australia Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, United Kingdom.
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D016054:DNA, Protozoan / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D016780:Malaria, Vivax / Q000188:drug therapy / Q000469:parasitology; D015767:Mefloquine / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D010966:Plasmodium vivax / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D013785:Thailand
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan; D015767:Mefloquine; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C541684:Mdr1 protein, Plasmodium vivax
keywords: Plasmodium vivax; Thailand; copy number; malaria; mdr1; mefloquine; multidrug resistance