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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya
PLoS ONE, Volume 9, No. 5, Article e96486, Year 2014
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Description
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.
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Authors & Co-Authors
Wendler, Jason P.
United Kingdom, Oxford
University of Oxford
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Okombo, John
Kenya, Nairobi
Kenya Medical Research Institute
Amato, Roberto
United Kingdom, Oxford
University of Oxford
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Miotto, Olivo
United Kingdom, Oxford
University of Oxford
Thailand, Nakhon Pathom
Mahidol University
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Kiara, Steven M.
Kenya, Nairobi
Kenya Medical Research Institute
Mwai, Leah
Kenya, Nairobi
Kenya Medical Research Institute
Pole, Lewa
Kenya, Nairobi
Kenya Medical Research Institute
O'Brien, John D.
United Kingdom, Oxford
University of Oxford
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Manske, Heinrich Magnus
United Kingdom, Hinxton
Wellcome Sanger Institute
Alcock, Dan
United Kingdom, Hinxton
Wellcome Sanger Institute
Drury, Eleanor
United Kingdom, Hinxton
Wellcome Sanger Institute
Sanders, Mandy J.
United Kingdom, Hinxton
Wellcome Sanger Institute
Oyola, Samuel O.
United Kingdom, Hinxton
Wellcome Sanger Institute
Malangone, Cinzia
United Kingdom, Hinxton
Wellcome Sanger Institute
Jyothi, Dushyanth
United Kingdom, Hinxton
Wellcome Sanger Institute
Miles, Alistair J.
United Kingdom, Oxford
University of Oxford
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Rockett, Kirk A.
United Kingdom, Oxford
University of Oxford
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
MacInnis, Bronwyn L.
United Kingdom, Oxford
University of Oxford
United Kingdom, Hinxton
Wellcome Sanger Institute
Marsh, Kevin
Kenya, Nairobi
Kenya Medical Research Institute
Bejon, Philip A.
United Kingdom, Oxford
University of Oxford
Kenya, Nairobi
Kenya Medical Research Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Nzila, Alexis M.
Saudi Arabia, Dhahran
King Fahd University of Petroleum and Minerals
Kwiatkowski, Dominic P.
United Kingdom, Oxford
University of Oxford
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Statistics
Citations: 26
Authors: 22
Affiliations: 6
Identifiers
Doi:
10.1371/journal.pone.0096486
e-ISSN:
19326203
Research Areas
Genetics And Genomics
Infectious Diseases
Maternal And Child Health
Study Locations
Kenya