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Genetic architecture of artemisinin-resistant Plasmodium falciparum.
Miotto, Olivo; Amato, Roberto; Ashley, Elizabeth A; MacInnis, Bronwyn; Almagro-Garcia, Jacob; Amaratunga, Chanaki; Lim, Pharath; Mead, Daniel; Oyola, Samuel O; Dhorda, Mehul; Imwong, Mallika; Woodrow, Charles; Manske, Magnus; Stalker, Jim; Drury, Eleanor; Campino, Susana; Amenga-Etego, Lucas; Thanh, Thuy-Nhien Nguyen; Tran, Hien Tinh; Ringwald, Pascal; Bethell, Delia; Nosten, Francois; Phyo, Aung Pyae; Pukrittayakamee, Sasithon; Chotivanich, Kesinee; Chuor, Char Meng; Nguon, Chea; Suon, Seila; Sreng, Sokunthea; Newton, Paul N; Mayxay, Mayfong; Khanthavong, Maniphone; Hongvanthong, Bouasy; Htut, Ye; Han, Kay Thwe; Kyaw, Myat Phone; Faiz, Md Abul; Fanello, Caterina I; Onyamboko, Marie; Mokuolu, Olugbenga A; Jacob, Christopher G; Takala-Harrison, Shannon; Plowe, Christopher V; Day, Nicholas P; Dondorp, Arjen M; Spencer, Chris C A; McVean, Gilean; Fairhurst, Rick M; White, Nicholas J; Kwiatkowski, Dominic P.
Afiliação
  • Miotto O; 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.
  • Amato R; 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.
  • Ashley EA; 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.
  • MacInnis B; 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
  • Almagro-Garcia J; 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.
  • Amaratunga C; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
  • Lim P; 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.
  • Mead D; Wellcome Trust Sanger Institute, Hinxton, UK.
  • Oyola SO; Wellcome Trust Sanger Institute, Hinxton, UK.
  • Dhorda M; 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
  • Imwong M; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Woodrow C; 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.
  • Manske M; 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
  • Stalker J; 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
  • Drury E; Wellcome Trust Sanger Institute, Hinxton, UK.
  • Campino S; 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
  • Amenga-Etego L; 1] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [2] Navrongo Health Research Centre, Navrongo, Ghana.
  • Thanh TN; Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
  • Tran HT; 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.
  • Ringwald P; Global Malaria Programme, World Health Organization, Geneva, Switzerland.
  • Bethell D; Department of Immunology and Medicine, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand.
  • Nosten F; 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 Uni
  • Phyo AP; 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 Uni
  • Pukrittayakamee S; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Chotivanich K; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Chuor CM; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
  • Nguon C; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
  • Suon S; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
  • Sreng S; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
  • Newton PN; 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.
  • Mayxay M; 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.
  • Khanthavong M; Center of Malariology, Parasitology and Entomology, Ministry of Health, Vientiane, Laos.
  • Hongvanthong B; Center of Malariology, Parasitology and Entomology, Ministry of Health, Vientiane, Laos.
  • Htut Y; Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
  • Han KT; Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
  • Kyaw MP; Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
  • Faiz MA; Malaria Research Group and Dev Care Foundation, Dhaka, Bangladesh.
  • Fanello CI; 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.
  • Onyamboko M; 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.
  • Mokuolu OA; Department of Paediatrics and Child Health, University of Ilorin, Ilorin, Nigeria.
  • Jacob CG; Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Takala-Harrison S; Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Plowe CV; 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.
  • Day NP; 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.
  • Dondorp AM; 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.
  • Spencer CC; 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.
  • McVean G; 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.
  • Fairhurst RM; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
  • White NJ; 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.
  • Kwiatkowski DP; 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.
Nat Genet ; 47(3): 226-34, 2015 Mar.
Article em En | MEDLINE | ID: mdl-25599401
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Genoma de Protozoário / Artemisininas / Antimaláricos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Genoma de Protozoário / Artemisininas / Antimaláricos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article