title: Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia.
abstract: The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Takala-Harrison
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Jacob
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cummings
authors.forename: Olivo
authors.initials: O
authors.lastname: Miotto
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: Mark M
authors.initials: MM
authors.lastname: Fukuda
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.forename: Harald
authors.initials: H
authors.lastname: Noedl
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.forename: Delia
authors.initials: D
authors.lastname: Bethell
authors.forename: Youry
authors.initials: Y
authors.lastname: Se
authors.forename: Chanthap
authors.initials: C
authors.lastname: Lon
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Tyner
authors.forename: David L
authors.initials: DL
authors.lastname: Saunders
authors.forename: Duong
authors.initials: D
authors.lastname: Socheat
authors.forename: Frederic
authors.initials: F
authors.lastname: Ariey
authors.forename: Aung Pyae
authors.initials: AP
authors.lastname: Phyo
authors.forename: Peter
authors.initials: P
authors.lastname: Starzengruber
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fuehrer
authors.forename: Paul
authors.initials: P
authors.lastname: Swoboda
authors.forename: Kasia
authors.initials: K
authors.lastname: Stepniewska
authors.forename: Jennifer
authors.initials: J
authors.lastname: Flegg
authors.forename: Cesar
authors.initials: C
authors.lastname: Arze
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Cerqueira
authors.forename: Joana C
authors.initials: JC
authors.lastname: Silva
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ricklefs
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stephens
authors.forename: Matthew
authors.initials: M
authors.lastname: Adams
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Kenefic
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Bronwyn
authors.initials: B
authors.lastname: MacInnis
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Xin-zhuan
authors.initials: XZ
authors.lastname: Su
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
mesh_terms: D037621:Artemisinins / Q000494:pharmacology*; D001210:Asia, Southeastern; D004351:Drug Resistance / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D016013:Likelihood Functions; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010963:Plasmodium falciparum / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D012044:Regression Analysis; D012641:Selection, Genetic
chemical_list: D037621:Artemisinins; D005819:Genetic Markers; C031327:artemisinin