Complex polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 gene and its contribution to antimalarial response

Plasmodium falciparum has the capacity to escape essentially all antimalarial drugs action. ATP-binding cassette (ABC) transporter proteins are known to be causative of multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for 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 Thai isolates. A notably high frequency of 2.8 single nucleotide polimorphisms (SNPs)/Kb was identified in this gene, with some SNPs being novel. Additionally, we also report that Pfmrp2 harbours a significant number of micro-indels, some previously not reported. We then investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in the artemisinin based combination therapy and with the parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms to modulate the parasite 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.