A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms.
A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms.
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恶性疟原虫 K13-Propeller 多态性的全球地图。
DOI：
10.1056/nejmoa1513137
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发表时间：
2016-06-23
期刊：
影响因子：
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通讯作者：
KARMA Consortium
中科院分区：
文献类型：
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作者：
Ménard D;Khim N;Beghain J;Adegnika AA;Shafiul-Alam M;Amodu O;Rahim-Awab G;Barnadas C;Berry A;Boum Y;Bustos MD;Cao J;Chen JH;Collet L;Cui L;Thakur GD;Dieye A;Djallé D;Dorkenoo MA;Eboumbou-Moukoko CE;Espino FE;Fandeur T;Ferreira-da-Cruz MF;Fola AA;Fuehrer HP;Hassan AM;Herrera S;Hongvanthong B;Houzé S;Ibrahim ML;Jahirul-Karim M;Jiang L;Kano S;Ali-Khan W;Khanthavong M;Kremsner PG;Lacerda M;Leang R;Leelawong M;Li M;Lin K;Mazarati JB;Ménard S;Morlais I;Muhindo-Mavoko H;Musset L;Na-Bangchang K;Nambozi M;Niaré K;Noedl H;Ouédraogo JB;Pillai DR;Pradines B;Quang-Phuc B;Ramharter M;Randrianarivelojosia M;Sattabongkot J;Sheikh-Omar A;Silué KD;Sirima SB;Sutherland C;Syafruddin D;Tahar R;Tang LH;Touré OA;Tshibangu-wa-Tshibangu P;Vigan-Womas I;Warsame M;Wini L;Zakeri S;Kim S;Eam R;Berne L;Khean C;Chy S;Ken M;Loch K;Canier L;Duru V;Legrand E;Barale JC;Stokes B;Straimer J;Witkowski B;Fidock DA;Rogier C;Ringwald P;Ariey F;Mercereau-Puijalon O;KARMA Consortium
背景
最近在减少全球疟疾负担方面取得的进展受到恶性疟原虫对青蒿素产生抗药性的威胁。恶性疟原虫基因编码kelch（K13）-螺旋桨结构域的部分突变是耐药性的主要决定因素，这一发现为在全球范围内监测此类耐药性提供了机会。
方法
我们分析了在疟疾流行的59个国家收集的14，037个样本中的K13螺旋桨序列多态性。大多数样本（84.5%）来自在用于全国抗疟药耐药性监测的哨点接受治疗的患者。我们通过对邻近位点进行单倍型分析来评估突变的出现和传播。
结果
我们确定了108个非同义K13突变，其频率和分布存在明显的地理差异。在亚洲，36.5%的K13突变分布在两个地区-一个在柬埔寨，越南和老挝，另一个在泰国西部，缅甸和中国-没有重叠。在非洲，我们观察到一系列罕见的非同义突变，这些突变与寄生虫清除延迟无关。具有A578 S突变的基因编辑的Dd 2转基因株系表达最常见的非洲等位基因，在体外环期存活试验中发现对青蒿素敏感。
结论
在东南亚和中国以外的地区没有发现青蒿素耐药性的证据，这些地区与耐药性相关的K13突变被限制。常见的非洲A578 S等位基因与临床或体外青蒿素耐药性无关，许多非洲突变似乎是中性的。（由巴斯德研究所巴黎和其他机构资助）。
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.).