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A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms.

Didier Ménard 1 Nimol Khim 1 Johann Beghain 2 Ayola A Adegnika 3, 4, 5 Mohammad Shafiul-Alam 6 Olukemi Amodu 7 Ghulam Rahim-Awab 8, 9 Céline Barnadas 10, 11, 12 Antoine Berry 13 Yap Boum 14, 15 Maria D Bustos 16 Jun Cao 17 Jun-Hu Chen 18 Louis Collet 19 Liwang Cui 20 Garib-Das Thakur 21 Alioune Dieye 22, 23 Djibrine Djallé 24 Monique A Dorkenoo 25 Carole E Eboumbou-Moukoko 26, 27 Fe-Esperanza-Caridad J Espino 28 Thierry Fandeur 29 Maria-Fatima Ferreira-Da-Cruz 30 Abebe A Fola 31, 10 Hans-Peter Fuehrer 32 Abdillahi M Hassan 33 Socrates Herrera 34 Bouasy Hongvanthong 35 Sandrine Houzé 36, 37 Maman L Ibrahim 38 Mohammad Jahirul-Karim 39 Lubin Jiang 40 Shigeyuki Kano 41, 42 Wasif Ali-Khan 6 Maniphone Khanthavong 35 Peter G Kremsner 3, 4 Marcus Lacerda 43, 44 Rithea Leang 45 Mindy Leelawong 46, 47 Mei Li 18 Khin Lin 48 Jean-Baptiste Mazarati 49 Sandie Ménard 50 Isabelle Morlais 51 Hypolite Muhindo-Mavoko 52, 53 Lise Musset 54 Kesara Na-Bangchang 55 Michael Nambozi 56 Karamoko Niaré 57 Harald Noedl 58 Jean-Bosco Ouédraogo 59 Dylan R Pillai 60, 61 Bruno Pradines 62, 63 Bui Quang-Phuc 35 Michael Ramharter 58, 4, 5 Milijaona Randrianarivelojosia 64 Jetsumon Sattabongkot 9 Abdiqani Sheikh-Omar 65 Kigbafori D Silué 66, 67 Sodiomon B Sirima 68 Colin Sutherland 69 Din Syafruddin 70, 71 Rachida Tahar 37 Lin-Hua Tang 18 Offianan A Touré 72 Patrick Tshibangu-Wa-Tshibangu 52 Inès Vigan-Womas 64 Marian Warsame 61 Lyndes Wini 73 Sedigheh Zakeri 74 Saorin Kim 1 Rotha Eam 1 Laura Berne 1 Chanra Khean 1 Sophy Chy 1 Malen Ken 1 Kaknika Loch 1 Lydie Canier 1 Valentine Duru 1 Eric Legrand 2, 54, 75 Jean-Christophe Barale 76 Barbara Stokes 77 Judith Straimer 77 Benoit Witkowski 1 David A Fidock 77 Christophe Rogier 62, 64, 78 Pascal Ringwald 61 Frederic Ariey 79, 80, 2 Odile Mercereau-Puijalon 2
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.).
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Submitted on : Thursday, June 23, 2016 - 11:07:09 AM
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Didier Ménard, Nimol Khim, Johann Beghain, Ayola A Adegnika, Mohammad Shafiul-Alam, et al.. A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms.. New England Journal of Medicine, Massachusetts Medical Society, 2016, 374 (25), pp.2453-64. ⟨10.1056/NEJMoa1513137⟩. ⟨pasteur-01336483⟩

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