Publication:
Genetic architecture of artemisinin-resistant Plasmodium falciparum

Issued Date

2015-02-25

Resource Type

Article

ISSN

15461718
10614036

DOI

10.1038/ng.3189

Other identifier(s)

2-s2.0-84924080547

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Nature Genetics. Vol.47, No.3 (2015), 226-234

Suggested Citation

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 Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nature Genetics. Vol.47, No.3 (2015), 226-234. doi:10.1038/ng.3189 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/35496

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Title

Genetic architecture of artemisinin-resistant Plasmodium falciparum

Author(s)

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

Other Contributor(s)

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

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.

Keyword(s)

Biochemistry, Genetics and Molecular Biology

Availability

URI

https://repository.li.mahidol.ac.th/handle/123456789/35496

Collections

Scopus 2011-2015