Genomic Analysis Reveals a Common Breakpoint in Amplifications of the Plasmodium vivax Multidrug Resistance 1 Locus in Thailand

• Published in: The Journal of infectious diseases 2016-10, Vol.214 (8), p.1235-1242
• Main Authors: Auburn, Sarah, Serre, David, Pearson, Richard D., Amato, Roberto, Sriprawat, Kanlaya, To, Sheren, Handayuni, Irene, Suwanarusk, Rossarin, Russell, Bruce, Drury, Eleanor, Stalker, Jim, Miotto, Olivo, Kwiatkowski, Dominic P., Nosten, Francois, Price, Ric N.
• Format: Article
• Language: English
• Subjects: Antimalarials - pharmacology; DNA, Protozoan - genetics; Drug Resistance, Multiple - genetics; Gene Dosage - genetics; Genomics - methods; Genotype; Humans; Major and Brief Reports; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Malaria, Vivax - drug therapy; Malaria, Vivax - parasitology; Mefloquine - pharmacology; Membrane Transport Proteins - genetics; Multidrug Resistance-Associated Proteins - genetics; PARASITES; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium vivax - drug effects; Plasmodium vivax - genetics; Protozoan Proteins - genetics; Thailand
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiw323

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 (pvmdr 1) 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 pvmdr 1amplification 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 pvmdr 1 amplification in other geographic regions will yield information about the population-specificity of the breakpoints and underlying amplification mechanisms.