Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study.
Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study.
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与柬埔寨恶性疟原虫疟疾双氢青蒿素-哌喹失败相关的遗传标记：基因型-表型关联研究。
DOI：
10.1016/s1473-3099(16)30409-1
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Fairhurst RM
中科院分区：
文献类型：
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作者：
Amato R;Lim P;Miotto O;Amaratunga C;Dek D;Pearson RD;Almagro-Garcia J;Neal AT;Sreng S;Suon S;Drury E;Jyothi D;Stalker J;Kwiatkowski DP;Fairhurst RM
随着大湄公河次区域对青蒿素具有抗药性的恶性疟原虫疟疾的流行率上升，对青蒿素综合疗法中的伙伴药物出现抗药性，严重威胁到全球治疗和消除这一疾病的努力。ACT失败的分子标志物迫切需要监测伴侣耐药性的传播，并在东南亚及其他地区推荐替代治疗。我们对来自柬埔寨的297株恶性疟原虫分离株进行了全基因组关联研究（GWAS），以调查11，630个外显子单核苷酸多态性（SNP）和43个拷贝数变异（CNV）与体外哌喹50%抑制浓度（IC 50）的关系，并测试这些遗传变异是否是双氢青蒿素-哌喹失败的标志物。然后，我们对133例患者进行了生存分析，以确定候选分子标记物是否预测双氢青蒿素-哌喹治疗后寄生虫复发。2011年至2013年，柬埔寨3个省的喹喹半数致死浓度显著增加。全基因组SNP分析确定了与哌喹IC 50升高相关的13号染色体区域。在编码核酸外切酶的基因内，该区域中的非同义SNP（编码Glu 415 Gly取代）与双氢青蒿素-哌喹治疗后的寄生虫复发相关。对CNVs的全基因组分析显示，5号染色体上mdr 1基因的单拷贝和14号染色体上plasmepsin II和plasmepsin III基因的新扩增也与哌喹IC 50升高相关。在调整协变量后，exo-E415 G和plasmepsin II-III标志物均与治疗疗效降低显著相关（分别为0.38和0.41的存活率）。exo-E415 G SNP和plasmepsin II-III扩增是柬埔寨哌喹耐药和双氢青蒿素-哌喹失败的标志物，可以帮助监测这些表型向GMS国家的传播，并阐明哌喹耐药的机制。由于plasmepsin参与寄生虫的血红蛋白到疟原虫色素的转化途径，相关抗疟药的靶向，plasmepsin II-III扩增可能介导哌喹耐药性。美国国立过敏和传染病研究所、国立卫生研究院、惠康信托基金会、比尔和梅林达盖茨基金会、医学研究理事会和英国国际发展部的校内研究计划。
As the prevalence of artemisinin-resistant Plasmodium falciparum malaria increases in the Greater Mekong Subregion (GMS), emerging resistance to partner drugs in artemisinin combination therapies (ACTs) seriously threatens global efforts to treat and eliminate this disease. Molecular markers for ACT failure are urgently needed to monitor the spread of partner drug resistance, and to recommend alternative treatments in Southeast Asia and beyond. We performed a genome-wide association study (GWAS) of 297 P. falciparum isolates from Cambodia to investigate the relationship of 11,630 exonic single-nucleotide polymorphisms (SNPs) and 43 copy number variations (CNVs) with in-vitro piperaquine 50% inhibitory concentrations (IC50s), and tested whether these genetic variants are markers of dihydroartemisinin-piperaquine failures. We then performed a survival analysis of 133 patients to determine whether candidate molecular markers predicted parasite recrudescence following dihydroartemisinin-piperaquine treatment. Piperaquine IC50s increased significantly from 2011 to 2013 in 3 Cambodian provinces. Genome-wide analysis of SNPs identified a chromosome 13 region that associates with elevated piperaquine IC50s. A nonsynonymous SNP (encoding a Glu415Gly substitution) in this region, within a gene encoding an exonuclease, associates with parasite recrudescence following dihydroartemisinin-piperaquine treatment. Genome-wide analysis of CNVs revealed that a single copy of the mdr1 gene on chromosome 5 and a novel amplification of the plasmepsin II and plasmepsin III genes on chromosome 14 also associate with elevated piperaquine IC50s. After adjusting for covariates, both exo-E415G and plasmepsin II-III markers significantly associate with decreased treatment efficacy (0.38 and 0.41 survival rates, respectively). The exo-E415G SNP and plasmepsin II-III amplification are markers of piperaquine resistance and dihydroartemisinin-piperaquine failures in Cambodia, and can help monitor the spread of these phenotypes into GMS countries, and elucidate the mechanism of piperaquine resistance. Since plasmepsins are involved in the parasite’s haemoglobin-to-haemozoin conversion pathway, targeted by related antimalarials, plasmepsin II-III amplification likely mediates piperaquine resistance. Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, National Institutes of Health; Wellcome Trust; Bill and Melinda Gates Foundation; Medical Research Council; and UK Department for International Development.