Genome-wide studies to identify markers of artemisinin-resistant malaria

全基因组研究以确定青蒿素耐药性疟疾的标志物

基本信息

批准号：
9011992
负责人：
SHANNON Takala Harrison
金额：
$ 45.48万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9011992
关键词：
Adopted Algorithms Antimalarials Area Artemisinins Biological Assay Cambodia Candidate Disease Gene Chloroquine resistance Chromosomes Clinical Research Clinical Trials Combined Modality Therapy Conduct Clinical Trials Containment Country Data Development Disease Drug usage Falciparum Malaria Folic Acid Antagonists Genes Genetic Genetic Polymorphism Genetic screening method Genome Genomic Segment Genotype Goals Half-Life Health Investments Laos Location Malaria Maps Measures Meta-Analysis Molecular Mutation Myanmar Outcome Parasite resistance Parasitemia Parasites Pharmaceutical Preparations Phenotype Pilot Projects Plasmodium falciparum Population Population Control Reading Reporting Resistance Sampling Single Nucleotide Polymorphism Site Southeastern Asia Thailand Time Vietnam Work analytical method artemisinine artesunate base candidate marker clinical phenotype curative treatments genome wide association study genome-wide analysis molecular marker next generation sequencing parasite genome response tool

项目摘要

DESCRIPTION (provided by applicant): Highly effective artemisinin-based antimalarial drugs are used worldwide and have contributed to reductions in the malaria burden in many areas. Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and its potential spread threatens to reverse recent gains against malaria and to abort plans for a renewed global eradication campaign. Ongoing efforts to contain artemisinin-resistant malaria are hampered by the lack of tools to gauge the extent and direction of its spread. Presently, only laborious clinical trials can reliably measure resistance. A molecular assay to detect markers of artemisinin resistance would be a highly valuable surveillance tool, but the genetic basis of resistance is unknown. We propose genome-wide association studies (GWAS) that aim to identify molecular markers that can be used to track and contain artemisinin-resistant parasites before they spread globally. The work will be accomplished in two aims. First, we will use a dense panel of single nucleotide polymorphisms (SNPs) to map regions of the P. falciparum genome that are associated with artemisinin resistance. To accomplish this, we will use an established SNP- calling pipeline to determine genotypes at ~421,000 SNPs from short-read sequencing data in parasites collected during completed trials of artemisinin efficacy, and we will estimate the association between parasite genotypes and the amount of time it takes to reduce parasitemia by half following artemisinin treatment (i.e. parasite clearance half-life). Associations will be estimated in two independent sample sets, and meta-analysis will be performed to validate genomic regions associated with artemisinin resistance. In the second aim, we will identify and prioritize candidate genes within genomic regions identified in Aim 1 and use next-generation sequencing data to identify polymorphisms within high-priority genes and their association with parasite clearance half-life. If successful, this project will result in the development of a rapid assay to detect candidate markers of artemisinin resistance in subsequent candidate gene association studies, as well as data to begin the functional characterization of candidate genes to better understand the mechanisms underlying resistance.

描述（由申请人提供）：高效的基于青蒿素的抗疟药在世界范围内使用，并导致许多地区的疟疾负担减轻。抗蒿属疟原虫恶性疟疾疟疾已经出现在西部柬埔寨，其潜在蔓延有可能扭转最近对疟疾的收益，并流产为重新获得全球消除运动的计划。缺乏衡量其传播的程度和方向的工具，阻碍了持续抗甲半氨酸蛋白疟疾的持续努力。目前，只有费力的临床试验才能可靠地衡量阻力。一种用于检测青蒿素耐药性标记的分子测定方法将是一种高度有价值的监视工具，但抗药性的遗传基础尚不清楚。我们提出了全基因组关联研究（GWAS），旨在鉴定可用于跟踪和含有甲r可动蛋白抗性寄生虫的分子标记，然后它们在全球范围内传播。这项工作将以两个目标完成。首先，我们将使用密集的单核苷酸多态性（SNP）来绘制与青蒿素耐药性相关的恶性疟原虫基因组的区域。 To accomplish this, we will use an established SNP- calling pipeline to determine genotypes at ~421,000 SNPs from short-read sequencing data in parasites collected during completed trials of artemisinin efficacy, and we will estimate the association between parasite genotypes and the amount of time it takes to reduce parasitemia by half following artemisinin treatment (i.e. parasite clearance half-life).将在两个独立的样本集中估算关联，并将进行荟萃分析以验证与青蒿素抗性相关的基因组区域。在第二个目标中，我们将确定并确定AIM 1中鉴定的基因组区域内的候选基因，并使用下一代测序数据来鉴定高优先级基因内的多态性，并与它们与寄生虫清除半衰期的关联。如果成功的话，该项目将导致快速测定的发展，以检测随后的候选基因关联研究中青蒿素抵抗的候选标志物，以及数据开始对候选基因的功能表征，以更好地了解耐药性的机制。