Association of a Novel Mutation in the Plasmodium falciparum Chloroquine Resistance Transporter With Decreased Piperaquine Sensitivity.

Published

Journal Article

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 33716 genome-wide 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.

Full Text

Duke Authors

Cited Authors

  • Agrawal, S; Moser, KA; Morton, L; Cummings, MP; Parihar, A; Dwivedi, A; Shetty, AC; Drabek, EF; Jacob, CG; Henrich, PP; Parobek, CM; Jongsakul, K; Huy, R; Spring, MD; Lanteri, CA; Chaorattanakawee, S; Lon, C; Fukuda, MM; Saunders, DL; Fidock, DA; Lin, JT; Juliano, JJ; Plowe, CV; Silva, JC; Takala-Harrison, S

Published Date

  • August 2017

Published In

Volume / Issue

  • 216 / 4

Start / End Page

  • 468 - 476

PubMed ID

  • 28931241

Pubmed Central ID

  • 28931241

Electronic International Standard Serial Number (EISSN)

  • 1537-6613

International Standard Serial Number (ISSN)

  • 0022-1899

Digital Object Identifier (DOI)

  • 10.1093/infdis/jix334

Language

  • eng