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J Infect Dis. 2015 Mar 1;211(5):670-9. doi: 10.1093/infdis/jiu491. Epub 2014 Sep 1.

Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.

Author information

1
Howard Hughes Medical Institute/Center for Vaccine Development.
2
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore.
3
Center for Bioinformatics and Computational Biology, University of Maryland, College Park.
4
Mahidol-Oxford Tropical Medicine Research Unit.
5
Armed Forces Research Institute of Medical Sciences, Bangkok.
6
Center for Tropical Medicine, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital Faculty of Postgraduate Studies, University of Health Sciences Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford.
8
Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria.
9
Mahidol-Oxford Tropical Medicine Research Unit Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford.
10
Department of Medical Research (Lower Myanmar), Yangon.
11
Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University.
12
Armed Forces Research Institute of Medical Sciences.
13
GGIV Unit, Parasitology and Mycology Departement.
14
Parasite Molecular Immunology Unit, Institut Pasteur, Paris, France.
15
Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
16
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford.
17
Center of Malariology, Parasitology, and Entomology, Vientiane, Laos.
18
International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
19
Mahidol-Oxford Tropical Medicine Research Unit Shoklo Malaria Research Unit Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
20
Research and Development, Roche NimbleGen, Madison, Wisconsin.
21
Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Indiana.
22
Faculty of Epidemiology and Population Health Faculty Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine.
23
Mahidol-Oxford Tropical Medicine Research Unit MRC Centre for Genomics and Global Health, Oxford University and Wellcome Trust Sanger Institute Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
24
Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
25
MRC Centre for Genomics and Global Health, Oxford University and Wellcome Trust Sanger Institute Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
26
Drug Resistance and Containment Unit, Global Malaria Programme, World Health Organization, Geneva, Switzerland.

Abstract

BACKGROUND:

The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia.

METHODS:

P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently.

RESULTS:

The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas.

CONCLUSIONS:

K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.

KEYWORDS:

Plasmodium falciparum; Southeast Asia; artemisinin resistance; kelch; malaria

PMID:
25180241
PMCID:
PMC4334802
DOI:
10.1093/infdis/jiu491
[Indexed for MEDLINE]
Free PMC Article
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