Open AccessA Genome Wide Association Study of Plasmodium falciparum Susceptibility to 22 Antimalarial Drugs in Kenya
Author(s) -
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 MacInnis,
Kevin Marsh,
Philip Bejon,
Alexis Nzila,
Dominic P. Kwiatkowski
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0096486
Subject(s) - plasmodium falciparum , biology , single nucleotide polymorphism , amodiaquine , malaria , dhps , drug resistance , genetics , genome wide association study , haplotype , pyrimethamine , piperaquine , sulfadoxine , chloroquine , genotype , dihydroartemisinin , virology , artemisinin , gene , immunology
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.