A worldwide map of Plasmodium falciparum K13-propeller polymorphisms

Didier Ménard, Nimol Khim, Johann Beghain, Ayola A. Adegnika, Mohammad Shafiul-Alam, Olukemi Amodu, Ghulam Rahim-Awab, Céline Barnadas, Antoine Berry, Yap Boum, Maria D. Bustos, Jun Cao, Jun Hu Chen, Louis Collet, Liwang Cui, Garib Das Thakur, Alioune Dieye, Djibrine Djallé, Monique A. Dorkenoo, Carole E. Eboumbou-MoukokoFe Esperanza Caridad J. Espino, Thierry Fandeur, Maria Fatima Ferreira-Da-Cruz, Abebe A. Fola, Hans Peter Fuehrer, Abdillahi M. Hassan, Socrates Herrera, Bouasy Hongvanthong, Sandrine Houzé, Maman L. Ibrahim, Mohammad Jahirul-Karim, Lubin Jiang, Shigeyuki Kano, Wasif Ali-Khan, Maniphone Khanthavong, Peter G. Kremsner, Marcus Lacerda, Rithea Leang, Mindy Leelawong, Mei Li, Khin Lin, Jean Baptiste Mazarati, Sandie Ménard, Isabelle Morlais, Hypolite Muhindo-Mavoko, Lise Musset, Kesara Na-Bangchang, Michael Nambozi, Karamoko Niaré, Harald Noedl, Jean Bosco Ouédraogo, Dylan R. Pillai, Bruno Pradines, Bui Quang-Phuc, Michael Ramharter, Milijaona Randrianarivelojosia, Jetsumon Sattabongkot, Abdiqani Sheikh-Omar, Kigbafori D. Silué, Sodiomon B. Sirima, Colin Sutherland, Din Syafruddin, Rachida Tahar, Lin Hua Tang, Offianan A. Touré, Patrick Tshibangu-Wa-Tshibangu, Inès Vigan-Womas, Marian Warsame, Lyndes Wini, Sedigheh Zakeri, Saorin Kim, Rotha Eam, Laura Berne, Chanra Khean, Sophy Chy, Malen Ken, Kaknika Loch, Lydie Canier, Valentine Duru, Eric Legrand, Jean Christophe Barale, Barbara Stokes, Judith Straimer, Benoit Witkowski, David A. Fidock, Christophe Rogier, Pascal Ringwald, Frederic Ariey, Odile Mercereau-Puijalon

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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.

Original languageEnglish (US)
Pages (from-to)2453-2464
Number of pages12
JournalNew England Journal of Medicine
Volume374
Issue number25
DOIs
StatePublished - Jun 23 2016

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Ménard, D., Khim, N., Beghain, J., Adegnika, A. A., Shafiul-Alam, M., Amodu, O., Rahim-Awab, G., Barnadas, C., Berry, A., Boum, Y., Bustos, M. D., Cao, J., Chen, J. H., Collet, L., Cui, L., Thakur, G. D., Dieye, A., Djallé, D., Dorkenoo, M. A., ... Mercereau-Puijalon, O. (2016). A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. New England Journal of Medicine, 374(25), 2453-2464. https://doi.org/10.1056/NEJMoa1513137