Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia
Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia
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DOI：
10.1073/pnas.1211205110
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发表时间：
2013-01-02
影响因子：
11.1
通讯作者：
Plowe, Christopher V.
中科院分区：
文献类型：
--
作者：
Takala-Harrison, Shannon;Clark, Taane G.;Plowe, Christopher V.
最近在柬埔寨西部出现了对青蒿素有抗药性的恶性疟原虫疟疾，这可能威胁到消灭疟疾的前景。确定耐药性的遗传基础将为分子监测提供工具，有助于遏制耐药性的努力。青蒿琥酯疗效的临床试验在孟加拉国、泰国西北部靠近缅甸边境的地区和柬埔寨西部的两个地点进行。从试验参与者收集的寄生虫使用恶性疟原虫特异性SNP阵列在8，079个单核苷酸多态性（SNP）进行基因分型。检查寄生虫基因型的最近正选择的特征和与寄生虫清除表型的关联，以确定与青蒿素抗性相关的基因组区域。染色体10（1）、13（2）和14（1）上的4个SNP与延迟寄生虫清除显著相关。13号染色体上的两个SNPs位于基因组的一个区域，该区域似乎在柬埔寨最近受到强烈的正选择。10号和13号染色体上的SNP位于参与复制后修复的基因中或附近，这是一种DNA损伤耐受途径。需要复制和验证研究来细化负责青蒿素耐药性的位点的位置，并了解其背后的机制;然而，10号和13号染色体上的两个SNP可能是东南亚青蒿素耐药性监测中延迟寄生虫清除的有用标记。
The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.