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Title: Genetic architecture of artemisinin-resistant Plasmodium falciparum
Authors: Olivo Miotto
Roberto Amato
Elizabeth A. Ashley
Bronwyn Macinnis
Jacob Almagro-Garcia
Chanaki Amaratunga
Pharath Lim
Daniel Mead
Samuel O. Oyola
Mehul Dhorda
Mallika Imwong
Charles Woodrow
Magnus Manske
Jim Stalker
Eleanor Drury
Susana Campino
Lucas Amenga-Etego
Thuy Nhien Nguyen Thanh
Hien Tinh Tran
Pascal Ringwald
Delia Bethell
Francois Nosten
Aung Pyae Phyo
Sasithon Pukrittayakamee
Kesinee Chotivanich
Char Meng Chuor
Chea Nguon
Seila Suon
Sokunthea Sreng
Paul N. Newton
Mayfong Mayxay
Maniphone Khanthavong
Bouasy Hongvanthong
Ye Htut
Kay Thwe Han
Myat Phone Kyaw
Md Abul Faiz
Caterina I. Fanello
Marie Onyamboko
Olugbenga A. Mokuolu
Christopher G. Jacob
Shannon Takala-Harrison
Christopher V. Plowe
Nicholas P. Day
Arjen M. Dondorp
Chris C.A. Spencer
Gilean Mcvean
Rick M. Fairhurst
Nicholas J. White
Dominic P. Kwiatkowski
Wellcome Trust Sanger Institute
University of Oxford
Mahidol University
Wellcome Trust Centre for Human Genetics
Nuffield Department of Clinical Medicine
National Institute of Allergy and Infectious Diseases
National Center for Parasitology, Entomology and Malaria Control
University of Maryland School of Medicine
Navrongo Health Research Center
Oxford University Clinical Research Unit
Organisation Mondiale de la Sante
Armed Forces Research Institute of Medical Sciences, Thailand
Mahosot Hospital
University of Health Sciences
Ministry of Health
Department of Medical Research
Dev Care Foundation
Kinshasa School of Public Health
University of Ilorin
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 25-Feb-2015
Citation: Nature Genetics. Vol.47, No.3 (2015), 226-234
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.
ISSN: 15461718
Appears in Collections:Scopus 2011-2015

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