title: Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya.
abstract: Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.
authors.affiliation: 1] KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya [2] Institute of Microbiology, Magdeburg University School of Medicine, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.forename: Judith
authors.initials: J
authors.lastname: Straimer
authors.forename: Leah
authors.initials: L
authors.lastname: Mwai
authors.forename: Abdirahman
authors.initials: A
authors.lastname: Abdi
authors.forename: Anja
authors.initials: A
authors.lastname: Rippert
authors.forename: John
authors.initials: J
authors.lastname: Okombo
authors.forename: Steven
authors.initials: S
authors.lastname: Muriithi
authors.forename: Philip
authors.initials: P
authors.lastname: Sasi
authors.forename: Moses Mosobo
authors.initials: MM
authors.lastname: Kortok
authors.forename: Brett
authors.initials: B
authors.lastname: Lowe
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Samuel
authors.initials: S
authors.lastname: Assefa
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Magnus
authors.initials: M
authors.lastname: Manske
authors.forename: Gareth
authors.initials: G
authors.lastname: Maslen
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D001483:Base Sequence; D016054:DNA, Protozoan / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D018503:Genome, Protozoan / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007630:Kenya; D016778:Malaria, Falciparum / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D016054:DNA, Protozoan; C039060:artenimol