title: Genetic architecture of artemisinin-resistant Plasmodium falciparum.
abstract: We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [3] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Olivo
authors.identifier: 0000000180606771
authors.initials: O
authors.lastname: Miotto
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [3] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Roberto
authors.identifier: 0000000186339221
authors.initials: R
authors.lastname: Amato
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: MacInnis
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [3] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Jacob
authors.initials: J
authors.lastname: Almagro-Garcia
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chanaki
authors.initials: C
authors.lastname: Amaratunga
authors.affiliation: 1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA. [2] National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mead
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Oyola
authors.affiliation: 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [2] Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA. [3] WorldWide Antimalarial Resistance Network (WWARN), Asia Regional Centre, Mahidol University, Bangkok, Thailand.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dhorda
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Woodrow
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
authors.forename: Magnus
authors.identifier: 0000000159160947
authors.initials: M
authors.lastname: Manske
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Stalker
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Drury
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.affiliation: 1] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [2] Navrongo Health Research Centre, Navrongo, Ghana.
authors.forename: Lucas
authors.initials: L
authors.lastname: Amenga-Etego
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
authors.forename: Thuy-Nhien Nguyen
authors.initials: TN
authors.lastname: Thanh
authors.affiliation: 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [2] Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
authors.forename: Hien Tinh
authors.initials: HT
authors.lastname: Tran
authors.affiliation: Global Malaria Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.affiliation: Department of Immunology and Medicine, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand.
authors.forename: Delia
authors.initials: D
authors.lastname: Bethell
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [3] Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [3] 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: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Sasithon
authors.identifier: 0000000325733967
authors.initials: S
authors.lastname: Pukrittayakamee
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Char Meng
authors.initials: CM
authors.lastname: Chuor
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Chea
authors.initials: C
authors.lastname: Nguon
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Seila
authors.initials: S
authors.lastname: Suon
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Sokunthea
authors.initials: S
authors.lastname: Sreng
authors.affiliation: 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [2] Lao Oxford Mahosot Wellcome Trust Research Unit (LOMWRU), Mahosot Hospital, Vientiane, Laos.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Newton
authors.affiliation: 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [2] Lao Oxford Mahosot Wellcome Trust Research Unit (LOMWRU), Mahosot Hospital, Vientiane, Laos. [3] Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Laos.
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.affiliation: Center of Malariology, Parasitology and Entomology, Ministry of Health, Vientiane, Laos.
authors.forename: Maniphone
authors.initials: M
authors.lastname: Khanthavong
authors.affiliation: Center of Malariology, Parasitology and Entomology, Ministry of Health, Vientiane, Laos.
authors.forename: Bouasy
authors.initials: B
authors.lastname: Hongvanthong
authors.affiliation: Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
authors.forename: Ye
authors.initials: Y
authors.lastname: Htut
authors.affiliation: Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
authors.forename: Kay Thwe
authors.initials: KT
authors.lastname: Han
authors.affiliation: Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
authors.forename: Myat Phone
authors.initials: MP
authors.lastname: Kyaw
authors.affiliation: Malaria Research Group and Dev Care Foundation, Dhaka, Bangladesh.
authors.forename: Md Abul
authors.initials: MA
authors.lastname: Faiz
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Caterina I
authors.initials: CI
authors.lastname: Fanello
authors.affiliation: 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [2] Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo.
authors.forename: Marie
authors.initials: M
authors.lastname: Onyamboko
authors.affiliation: Department of Paediatrics and Child Health, University of Ilorin, Ilorin, Nigeria.
authors.forename: Olugbenga A
authors.initials: OA
authors.lastname: Mokuolu
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Jacob
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Takala-Harrison
authors.affiliation: 1] Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA. [2] Howard Hughes Medical Institute, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: 1] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Chris C A
authors.initials: CC
authors.lastname: Spencer
authors.affiliation: 1] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [3] Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: Gilean
authors.initials: G
authors.lastname: McVean
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [3] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018503:Genome, Protozoan; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin