A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.
<h4>Background</h4>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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0096486 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850124872104017920 |
|---|---|
| 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_facet | 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 |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods and principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format | Article |
| id | doaj-art-d32bcf6025e640c29e09d66f4d6a85d5 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d32bcf6025e640c29e09d66f4d6a85d52025-08-20T02:34:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9648610.1371/journal.pone.0096486A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.Jason P WendlerJohn OkomboRoberto AmatoOlivo MiottoSteven M KiaraLeah MwaiLewa PoleJohn O'BrienMagnus ManskeDan AlcockEleanor DruryMandy SandersSamuel O OyolaCinzia MalangoneDushyanth JyothiAlistair MilesKirk A RockettBronwyn L MacInnisKevin MarshPhilip BejonAlexis NzilaDominic P Kwiatkowski<h4>Background</h4>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.<h4>Methods and principal findings</h4>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.<h4>Conclusions/significance</h4>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.https://doi.org/10.1371/journal.pone.0096486 |
| spellingShingle | 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. PLoS ONE |
| title | 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_short | 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 |
| url | https://doi.org/10.1371/journal.pone.0096486 |
| work_keys_str_mv | AT jasonpwendler agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT johnokombo agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT robertoamato agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT olivomiotto agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT stevenmkiara agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT leahmwai agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT lewapole agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT johnobrien agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT magnusmanske agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT danalcock agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT eleanordrury agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT mandysanders agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT samuelooyola agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT cinziamalangone agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT dushyanthjyothi agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT alistairmiles agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT kirkarockett agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT bronwynlmacinnis agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT kevinmarsh agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT philipbejon agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT alexisnzila agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT dominicpkwiatkowski agenomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT jasonpwendler genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT johnokombo genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT robertoamato genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT olivomiotto genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT stevenmkiara genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT leahmwai genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT lewapole genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT johnobrien genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT magnusmanske genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT danalcock genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT eleanordrury genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT mandysanders genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT samuelooyola genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT cinziamalangone genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT dushyanthjyothi genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT alistairmiles genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT kirkarockett genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT bronwynlmacinnis genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT kevinmarsh genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT philipbejon genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT alexisnzila genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya AT dominicpkwiatkowski genomewideassociationstudyofplasmodiumfalciparumsusceptibilityto22antimalarialdrugsinkenya |