A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya
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...
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th-mahidol.330212018-11-09T08:52:47Z A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya 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 Agricultural and Biological Sciences Biochemistry, Genetics and Molecular Biology 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. 2018-11-09T01:44:45Z 2018-11-09T01:44:45Z 2014-05-08 Article PLoS ONE. Vol.9, No.5 (2014) 10.1371/journal.pone.0096486 19326203 2-s2.0-84901490769 https://repository.li.mahidol.ac.th/handle/123456789/33021 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84901490769&origin=inward |
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Agricultural and Biological Sciences Biochemistry, Genetics and Molecular Biology 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 A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya |
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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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University of Oxford |
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University of Oxford 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 |
format |
Article |
author |
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 |
author_sort |
Jason P. Wendler |
title |
A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya |
title_short |
A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya |
title_full |
A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya |
title_fullStr |
A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya |
title_full_unstemmed |
A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya |
title_sort |
genome wide association study of plasmodium falciparum susceptibility to 22 antimalarial drugs in kenya |
publishDate |
2018 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/33021 |
_version_ |
1763488753408540672 |