Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response

<jats:title>ABSTRACT</jats:title><jats:p><jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>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<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Apicomplexa</jats:named-content>parasites.<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters:<jats:italic>Pfmrp1</jats:italic>, previously associated with decreased parasite drug susceptibility, and the poorly studied<jats:italic>Pfmrp2</jats:italic>. The role of<jats:italic>Pfmrp2</jats:italic>polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the<jats:italic>Pfmrp2</jats:italic>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<jats:italic>Pfmrp2</jats:italic>harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified<jats:italic>Pfmrp2</jats:italic>polymorphisms with altered<jats:italic>in vitro</jats:italic>susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested<jats:italic>Pfmrp2</jats:italic>polymorphisms modulate the parasite's<jats:italic>in vitro</jats:italic>response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with<jats:italic>in vivo</jats:italic>parasite clearance. In conclusion, our study reveals that the<jats:italic>Pfmrp2</jats:italic>gene is the most diverse ABC transporter known in<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>with a potential role in antimalarial drug resistance.</jats:p>