Author
Affilliation
Abstract
BACKGROUND
Recent gains in reducing the global burden of malaria are threatened by the emergence of
Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions
of a P. falciparum gene encoding kelch (K13)–propeller domains are the major determinant
of resistance has provided opportunities for monitoring such resistance on a global scale.
METHODS
We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in
59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained
from patients who were treated at sentinel sites used for nationwide surveillance of
antimalarial resistance. We evaluated the emergence and dissemination of mutations
by haplotyping neighboring loci.
RESULTS
We identified 108 nonsynonymous K13 mutations, which showed marked geographic
disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were
distributed within two areas — one in Cambodia, Vietnam, and Laos and the other in
western Thailand, Myanmar, and China — with no overlap. In Africa, we observed a
broad array of rare nonsynonymous mutations that were not associated with delayed
parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which
expresses the most frequently observed African allele, was found to be susceptible to
artemisinin in vitro on a ring-stage survival assay.
CONCLUSIONS
No evidence of artemisinin resistance was found outside Southeast Asia and China,
where resistance-associated K13 mutations were confined. The common African A578S
allele was not associated with clinical or in vitro resistance to artemisinin, and many
African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others.
Publisher
Massachusetts Medical Society
Citation
MÉNARD, D. et al. A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms. The New England Journal of Medicine, 374:25, p.2453-2464, June 2016.
DOI
10.1056/NEJMoa1513137
ISSN
0028-4793
Notes
The authors’ full names and academic degrees are as follows: Didier Ménard, Ph.D., Nimol Khim, Ph.D., Johann Beghain, M.Sc.,
Ayola A. Adegnika, M.D., Ph.D., Mohammad Shafiul-Alam, Ph.D., Olukemi Amodu, Ph.D., Ghulam Rahim-Awab, Ph.D., Céline Barnadas,
Ph.D., Antoine Berry, M.D., Ph.D., Yap Boum, Ph.D., Maria D. Bustos, M.D., Ph.D., Jun Cao, Ph.D., Jun-Hu Chen, Ph.D., Louis
Collet, M.D., Liwang Cui, Ph.D., Garib-Das Thakur, M.D., Alioune Dieye, Pharm.D., Ph.D., Djibrine Djallé, M.Sc., Monique A. Dorkenoo,
M.D., Carole E. Eboumbou-Moukoko, Ph.D., Fe-Esperanza-Caridad J. Espino, M.D., Ph.D., Thierry Fandeur, Ph.D., Maria-Fatima
Ferreira-da-Cruz, Ph.D., Abebe A. Fola, M.Sc., Hans-Peter Fuehrer, Ph.D., Abdillahi M. Hassan, B.Sc., Socrates Herrera, M.D., Bouasy
Hongvanthong, M.D., Sandrine Houzé, M.D., Ph.D., Maman L. Ibrahim, M.V.D., Ph.D., Mohammad Jahirul-Karim, M.B., B.S., Lubin
Jiang, Ph.D., Shigeyuki Kano, M.D., Ph.D., Wasif Ali-Khan, M.B., B.S., Maniphone Khanthavong, M.D., Peter G. Kremsner, M.D.,
Marcus Lacerda, M.D., Ph.D., Rithea Leang, M.D., Mindy Leelawong, Ph.D., Mei Li, Ph.D., Khin Lin, M.D., Jean-Baptiste Mazarati,
Ph.D., Sandie Ménard, M.Sc., Isabelle Morlais, Ph.D., Hypolite Muhindo-Mavoko, M.D., Lise Musset, Pharm.D., Ph.D., Kesara
Na-Bangchang, Ph.D., Michael Nambozi, M.P.H., Karamoko Niaré, Pharm.D., Harald Noedl, M.D., Ph.D., Jean-Bosco Ouédraogo,
M.D., Ph.D., Dylan R. Pillai, M.D., Ph.D., Bruno Pradines, Pharm.D., Ph.D., Bui Quang-Phuc, M.D., Michael Ramharter, M.D.,
D.T.M.H., Milijaona Randrianarivelojosia, Ph.D., Jetsumon Sattabongkot, Ph.D., Abdiqani Sheikh-Omar, M.D., Kigbafori D. Silué, Ph.D., Sodiomon B. Sirima, M.D., Ph.D., Colin Sutherland, Ph.D., M.P.H., Din Syafruddin, M.D., Ph.D., Rachida Tahar, Ph.D., Lin-Hua
Tang, M.D., Ph.D., Offianan A. Touré, Ph.D., Patrick Tshibangu-wa-Tshibangu, M.D., Inès Vigan-Womas, Ph.D., Marian Warsame, M.D.,
Ph.D., Lyndes Wini, M.B., B.S., Sedigheh Zakeri, Ph.D., Saorin Kim, B.S., Rotha Eam, B.S., Laura Berne, M.Sc., Chanra Khean, B.S., Sophy
Chy, B.S., Malen Ken, B.S., Kaknika Loch, B.S., Lydie Canier, M.Sc., Valentine Duru, M.Sc., Eric Legrand, Ph.D., Jean-Christophe Barale,
Ph.D., Barbara Stokes, B.Sc., Judith Straimer, Ph.D., Benoit Witkowski, Ph.D., David A. Fidock, Ph.D., Christophe Rogier, M.D., Ph.D.,
Pascal Ringwald, M.D., Frederic Ariey, M.D., Ph.D., and Odile Mercereau-Puijalon, Ph.D.
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