Characterizing the impact of sustained sulfadoxine/pyrimethamine use upon the Plasmodium falciparum population in Malawi.
Characterizing the impact of sustained sulfadoxine/pyrimethamine use upon the Plasmodium falciparum population in Malawi.
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DOI：
10.1186/s12936-016-1634-6
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发表时间：
2016-11-29
期刊：
影响因子：
3
通讯作者：
Clark TG
中科院分区：
文献类型：
--
作者：
Ravenhall M;Benavente ED;Mipando M;Jensen AT;Sutherland CJ;Roper C;Sepúlveda N;Kwiatkowski DP;Montgomery J;Phiri KS;Terlouw A;Craig A;Campino S;Ocholla H;Clark TG
马拉维长期使用磺胺嘧啶/乙胺嘧啶作为一线抗疟疾药物，但过早地取代了氯喹，并推迟采用青蒿素类复方疗法。SP的长期使用及其在妊娠期的持续应用正在影响恶性疟原虫种群的基因组变异。使用了涵盖马拉维境内2年传播的恶性疟原虫分离株的全基因组序列数据以及全球数据集。超过745，000个SNPs被确定，并且评估了国家之间等位基因频率的差异，以及确定了正选择下的遗传区域。在dhps、dhfr和gch 1中鉴定出阳性选择信号，这些成分都是与SP抗性相关的寄生虫叶酸途径的组成部分。主要是在dhfr三重突变的背景下，在gch 1启动子中发现了一种新的拷贝数增加~ 2倍。这个拷贝数在马拉维样本中几乎是固定的（96.8%的频率），但在其他非洲人群中发现的频率低于45%，与以前在东南亚寄生虫中报道的整个基因重复不同。SP抗性选择压力已被保留在马拉维人口，与已知的抗性dhfr突变的固定，补充了一个新的gch 1启动子复制。复制对SP变异体和抗性的适应性成本的影响需要阐明。本文的在线版本（doi：10.1186/s12936-016-1634-6）包含补充材料，可供授权用户使用。
Malawi experienced prolonged use of sulfadoxine/pyrimethamine (SP) as the front-line anti-malarial drug, with early replacement of chloroquine and delayed introduction of artemisinin-based combination therapy. Extended use of SP, and its continued application in pregnancy is impacting the genomic variation of the Plasmodium falciparum population. Whole genome sequence data of P. falciparum isolates covering 2 years of transmission within Malawi, alongside global datasets, were used. More than 745,000 SNPs were identified, and differences in allele frequencies between countries assessed, as well as genetic regions under positive selection determined. Positive selection signals were identified within dhps, dhfr and gch1, all components of the parasite folate pathway associated with SP resistance. Sitting predominantly on a dhfr triple mutation background, a novel copy number increase of ~twofold was identified in the gch1 promoter. This copy number was almost fixed (96.8% frequency) in Malawi samples, but found at less than 45% frequency in other African populations, and distinct from a whole gene duplication previously reported in Southeast Asian parasites. SP resistance selection pressures have been retained in the Malawian population, with known resistance dhfr mutations at fixation, complemented by a novel gch1 promoter duplication. The effects of the duplication on the fitness costs of SP variants and resistance need to be elucidated. The online version of this article (doi:10.1186/s12936-016-1634-6) contains supplementary material, which is available to authorized users.
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DOI：
10.4269/ajtmh.13-0129
发表时间：
2013-11
期刊：
The American journal of tropical medicine and hygiene
影响因子：
--
作者：
Flegg JA;Metcalf CJE;Gharbi M;Venkatesan M;Shewchuk T;Hopkins Sibley C;Guerin PJ
通讯作者：
Guerin PJ
影响因子：
10.7
作者：
Gunasekera, Anusha M.;Wickramarachchi, Thilan;Wirth, Dyann F.
通讯作者：
Wirth, Dyann F.
影响因子：
3.7
作者：
Auburn S;Marfurt J;Maslen G;Campino S;Ruano Rubio V;Manske M;Machunter B;Kenangalem E;Noviyanti R;Trianty L;Sebayang B;Wirjanata G;Sriprawat K;Alcock D;Macinnis B;Miotto O;Clark TG;Russell B;Anstey NM;Nosten F;Kwiatkowski DP;Price RN
通讯作者：
Price RN
影响因子：
3.7
作者：
Auburn S;Campino S;Miotto O;Djimde AA;Zongo I;Manske M;Maslen G;Mangano V;Alcock D;MacInnis B;Rockett KA;Clark TG;Doumbo OK;Ouédraogo JB;Kwiatkowski DP
通讯作者：
Kwiatkowski DP
影响因子：
4.6
作者：
Borrmann S;Straimer J;Mwai L;Abdi A;Rippert A;Okombo J;Muriithi S;Sasi P;Kortok MM;Lowe B;Campino S;Assefa S;Auburn S;Manske M;Maslen G;Peshu N;Kwiatkowski DP;Marsh K;Nzila A;Clark TG
通讯作者：
Clark TG