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Genetic architecture of artemisinin-resistant Plasmodium falciparum.
- Source :
-
Nature genetics [Nat Genet] 2015 Mar; Vol. 47 (3), pp. 226-34. Date of Electronic Publication: 2015 Jan 19. - Publication Year :
- 2015
-
Abstract
- We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.
- Subjects :
- Drug Resistance genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study methods
Humans
Malaria, Falciparum drug therapy
Malaria, Falciparum parasitology
Mutation
Polymorphism, Single Nucleotide
Antimalarials pharmacology
Artemisinins pharmacology
Genome, Protozoan
Plasmodium falciparum drug effects
Plasmodium falciparum genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 47
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 25599401
- Full Text :
- https://doi.org/10.1038/ng.3189