Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.
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Takala-Harrison Shannon, Jacob Christopher G, Arze Cesar, Cummings Michael P, Silva Joana C, Dondorp Arjen M, Fukuda Mark M, Hien Tran Tinh, Mayxay Mayfong, Noedl Harald, Nosten Francois, Kyaw Myat P, Nhien Nguyen Thanh Thuy, Imwong Mallika, Bethell Delia, Se Youry, Lon Chanthap, Tyner Stuart D, Saunders David L, Ariey Frederic, Mercereau-Puijalon Odile, Menard Didier, Newton Paul N, Khanthavong Maniphone, Hongvanthong Bouasy, Starzengruber Peter, Fuehrer Hans-Peter, Swoboda Paul, Khan Wasif A, Phyo Aung Pyae, Nyunt Myaing M, Nyunt Myat H, Brown Tyler S, Adams Matthew, Pepin Christopher S, Bailey Jason, Tan John C, Ferdig Michael T, Clark Taane G, Miotto Olivo, MacInnis Bronwyn, Kwiatkowski Dominic P, White Nicholas J, Ringwald Pascal, Plowe Christopher V
Аннотация
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.