Association of a novel mutation in the plasmodium falciparum chloroquine resistance transporter with decreased piperaquine sensitivity

Sonia Agrawal, Kara A. Moser, Lindsay Morton, Michael P. Cummings, Ankita Parihar, Ankit Dwivedi, Amol C. Shetty, Elliott F. Drabek, Christopher G. Jacob, Philipp P. Henrich, Christian M. Parobek, Krisada Jongsakul, Rekol Huy, Michele D. Spring, Charlotte A. Lanteri, Suwanna Chaorattanakawee, Chanthap Lon, Mark M. Fukuda, David L. Saunders, David A. FidockJessica T. Lin, Jonathan J. Juliano, Christopher V. Plowe, Joana C. Silva, Shannon Takala-Harrison*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


Background. Amplified copy number in the plasmepsin II/III genes within Plasmodium falciparum has been associated with decreased sensitivity to piperaquine. To examine this association and test whether additional loci might also contribute, we performed a genome-wide association study of ex vivo P. falciparum susceptibility to piperaquine. Methods. Plasmodium falciparum DNA from 183 samples collected primarily from Cambodia was genotyped at 33 716 genomewide single nucleotide polymorphisms (SNPs). Linear mixed models and random forests were used to estimate associations between parasite genotypes and piperaquine susceptibility. Candidate polymorphisms were evaluated for their association with dihydroartemisinin- piperaquine treatment outcomes in an independent dataset. Results. Single nucleotide polymorphisms on multiple chromosomes were associated with piperaquine 90% inhibitory concentrations (IC90) in a genome-wide analysis. Fine-mapping of genomic regions implicated in genome-wide analyses identified multiple SNPs in linkage disequilibrium with each other that were significantly associated with piperaquine IC90, including a novel mutation within the gene encoding the P. falciparum chloroquine resistance transporter, PfCRT. This mutation (F145I) was associated with dihydroartemisinin-piperaquine treatment failure after adjusting for the presence of amplified plasmepsin II/III, which was also associated with decreased piperaquine sensitivity. Conclusions. Our data suggest that, in addition to plasmepsin II/III copy number, other loci, including pfcrt, may also be involved in piperaquine resistance.

Original languageEnglish
Pages (from-to)468-476
Number of pages9
JournalJournal of Infectious Diseases
Issue number4
StatePublished - 1 Aug 2017
Externally publishedYes


  • Chloroquine resistance transporter
  • Malaria
  • Piperaquine
  • Plasmepsin
  • Plasmodium falciparum
  • Resistance


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