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Nat Genet. 2015 Mar;47(3):226-34. doi: 10.1038/ng.3189. Epub 2015 Jan 19.

Genetic architecture of artemisinin-resistant Plasmodium falciparum.

Author information

1
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.
2
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.
3
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.
4
1] Wellcome Trust Sanger Institute, Hinxton, UK. [2] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
5
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
6
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.
7
Wellcome Trust Sanger Institute, Hinxton, UK.
8
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.
9
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
10
1] Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. [2] Navrongo Health Research Centre, Navrongo, Ghana.
11
Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
12
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.
13
Global Malaria Programme, World Health Organization, Geneva, Switzerland.
14
Department of Immunology and Medicine, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand.
15
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.
16
National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
17
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.
18
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.
19
Center of Malariology, Parasitology and Entomology, Ministry of Health, Vientiane, Laos.
20
Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
21
Malaria Research Group and Dev Care Foundation, Dhaka, Bangladesh.
22
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.
23
Department of Paediatrics and Child Health, University of Ilorin, Ilorin, Nigeria.
24
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
25
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.
26
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.
27
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.

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.

PMID:
25599401
PMCID:
PMC4545236
DOI:
10.1038/ng.3189
[Indexed for MEDLINE]
Free PMC Article

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