title: Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.
abstract: BACKGROUND
  The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia.
  
  
  METHODS
  P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently.
  
  
  RESULTS
  The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas.
  
  
  CONCLUSIONS
  K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Shannon
authors.initials: S
authors.lastname: Takala-Harrison
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Jacob
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore.
authors.forename: Cesar
authors.initials: C
authors.lastname: Arze
authors.affiliation: Center for Bioinformatics and Computational Biology, University of Maryland, College Park.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cummings
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore.
authors.forename: Joana C
authors.initials: JC
authors.lastname: Silva
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Fukuda
authors.affiliation: Center for Tropical Medicine, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital Faculty of Postgraduate Studies, University of Health Sciences Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford.
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.affiliation: Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Noedl
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Department of Medical Research (Lower Myanmar), Yangon.
authors.forename: Myat P
authors.initials: MP
authors.lastname: Kyaw
authors.affiliation: Center for Tropical Medicine, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Thanh Thuy
authors.initials: NT
authors.lastname: Nhien
authors.affiliation: Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University.
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok.
authors.forename: Delia
authors.initials: D
authors.lastname: Bethell
authors.affiliation: Armed Forces Research Institute of Medical Sciences.
authors.forename: Youry
authors.initials: Y
authors.lastname: Se
authors.affiliation: Armed Forces Research Institute of Medical Sciences.
authors.forename: Chanthap
authors.initials: C
authors.lastname: Lon
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Tyner
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok.
authors.forename: David L
authors.initials: DL
authors.lastname: Saunders
authors.affiliation: GGIV Unit, Parasitology and Mycology Departement.
authors.forename: Frederic
authors.initials: F
authors.lastname: Ariey
authors.affiliation: Parasite Molecular Immunology Unit, Institut Pasteur, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.affiliation: Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Didier
authors.initials: D
authors.lastname: Menard
authors.affiliation: Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Newton
authors.affiliation: Center of Malariology, Parasitology, and Entomology, Vientiane, Laos.
authors.forename: Maniphone
authors.initials: M
authors.lastname: Khanthavong
authors.affiliation: Center of Malariology, Parasitology, and Entomology, Vientiane, Laos.
authors.forename: Bouasy
authors.initials: B
authors.lastname: Hongvanthong
authors.affiliation: Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Starzengruber
authors.affiliation: Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fuehrer
authors.affiliation: Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Swoboda
authors.affiliation: International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
authors.forename: Wasif A
authors.initials: WA
authors.lastname: Khan
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit Shoklo Malaria Research Unit Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Aung Pyae
authors.initials: AP
authors.lastname: Phyo
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Myaing M
authors.initials: MM
authors.lastname: Nyunt
authors.affiliation: Department of Medical Research (Lower Myanmar), Yangon.
authors.forename: Myat H
authors.initials: MH
authors.lastname: Nyunt
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Brown
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Matthew
authors.initials: M
authors.lastname: Adams
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Pepin
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Jason
authors.initials: J
authors.lastname: Bailey
authors.affiliation: Research and Development, Roche NimbleGen, Madison, Wisconsin.
authors.forename: John C
authors.initials: JC
authors.lastname: Tan
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Indiana.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ferdig
authors.affiliation: Faculty of Epidemiology and Population Health Faculty Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit MRC Centre for Genomics and Global Health, Oxford University and Wellcome Trust Sanger Institute Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Olivo
authors.initials: O
authors.lastname: Miotto
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: MacInnis
authors.affiliation: MRC Centre for Genomics and Global Health, Oxford University and Wellcome Trust Sanger Institute Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Drug Resistance and Containment Unit, Global Malaria Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.affiliation: Howard Hughes Medical Institute/Center for Vaccine Development.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D001210:Asia, Southeastern; D004351:Drug Resistance; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; C031327:artemisinin
keywords: Plasmodium falciparum; Southeast Asia; artemisinin resistance; kelch; malaria