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

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

来源：Journal of Infectious Diseases, 2017, 216(4): 468-476.

DOI：10.1093/infdis/jix334

• malaria
• piperaquine
• resistance
• Plasmodium falciparum
• chloroquine resistance transporter
• plasmepsin

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 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 dihydroarte-misinin-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.

• 出版日期2017-8-15
• 单位上海生物信息技术研究中心; 河北医科大学