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Title: A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya
Authors: Jason P. Wendler
John Okombo
Roberto Amato
Olivo Miotto
Steven M. Kiara
Leah Mwai
Lewa Pole
John O'Brien
Magnus Manske
Dan Alcock
Eleanor Drury
Mandy Sanders
Samuel O. Oyola
Cinzia Malangone
Dushyanth Jyothi
Alistair Miles
Kirk A. Rockett
Bronwyn L. MacInnis
Kevin Marsh
Philip Bejon
Alexis Nzila
Dominic P. Kwiatkowski
University of Oxford
Kenya Medical Research Institute
Mahidol University
Wellcome Trust Sanger Institute
Wellcome Trust Centre for Human Genetics
King Fahd University of Petroleum and Minerals
Keywords: Agricultural and Biological Sciences;Biochemistry, Genetics and Molecular Biology
Issue Date: 8-May-2014
Citation: PLoS ONE. Vol.9, No.5 (2014)
Abstract: Background: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. Methods and Principal Findings: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. Conclusions/Significance: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ. © 2014 Wendler et al.
ISSN: 19326203
Appears in Collections:Scopus 2011-2015

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