Independent Emergence of Artemisinin Resistance Mutations Among Plasmodium falciparum in Southeast Asia
Year: 2014
Type: article
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.
Authors: Shannon Takala-Harrison, Christopher G. Jacob, Cesar Arze, Michael P. Cummings, Joana C. Silva, Arjen M. Dondorp, Mark M. Fukuda, Tran Tinh Hien, Mayfong Mayxay, Harald Noedl, Francois Nosten, Myat P. Kyaw, Nguyen Thanh Thuy Nhien, Mallika Imwong, Delia Bethell, Youry Se, Chanthap Lon, Stuart D. Tyner, David L. Saunders, Frederic Ariey, Odile Mercereau-Puijalon, Didier Menard, Paul N. Newton, Maniphone Khanthavong, Bouasy Hongvanthong, Peter Starzengruber, Hans-Peter Fuehrer, Paul Swoboda, Wasif A. Khan, Aung Pyae Phyo, Myaing M. Nyunt, Myat H. Nyunt, Tyler S. Brown, Matthew Adams, Christopher S. Pepin, Jason Bailey, John C. Tan, Michael T. Ferdig, Taane G. Clark, Olivo Miotto, Bronwyn MacInnis, Dominic P. Kwiatkowski, Nicholas J. White, Pascal Ringwald, Christopher V. Plowe
Institutions: Howard Hughes Medical Institute, University of Maryland, Baltimore, University of Maryland, College Park, Mahidol Oxford Tropical Medicine Research Unit, Armed Forces Research Institute of Medical Science, Oxford University Clinical Research Unit, University of Oxford, Sağlık Bilimleri Üniversitesi, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Medical University of Vienna, Mahidol University, Institut Pasteur, Institut Pasteur du Cambodge, International Centre for Diarrhoeal Disease Research, Shoklo Malaria Research Unit, University of Notre Dame, London School of Hygiene & Tropical Medicine, Wellcome Sanger Institute, World Health Organization
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, Howard Hughes Medical Institute, Doris Duke Charitable Foundation, World Health Organization, University of Notre Dame, Wellcome Trust, Mahidol University, National Institutes of Health, Medical Research Council, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: MRC Centre for Genomics and Global Health, Resource centre for genomic epidemiology of malaria., G4690106108, G499500337, A Genomics Based Investigation of the Determinants of Polymicrobial Infectious Disease Outcomes, Genome-wide studies to identify markers of artemisinin-resistant malaria, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., Expanding Participation by Minorities in Biomedical Sciences, Improving the treatment of malaria., Resource centre for genomic epidemiology of malaria., Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers, G8975541179
OpenAlex ID: W2104700616