Human copy number polymorphism and severe malaria

人类拷贝数多态性与严重疟疾

• 批准号: 8691715
• 负责人: JEFFREY A. BAILEY
• 金额: $ 59.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-27 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691715
• 关键词: 5 year old; Accounting; Acute; Affect; Africa; Africa South of the Sahara; African; Anemia; Autoimmune Diseases; Biological Assay; Candidate Disease Gene; Cataloging; Catalogs; Cerebral Malaria; Child; Clinical; Communicable Diseases; Complex; Copy Number Polymorphism; Custom; DNA; Discrimination; Disease; Ensure; Evolution; Frequencies; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Globin; Goals; Human; Human Genetics; Human Genome; Immune response; Individual; Infection; Kenya; Malaria; Malaria Vaccines; Measures; Morbidity - disease rate; Mutation; Natural Resistance; Parasites; Patients; Persons; Plasmodium falciparum; Population; Population Study; Predisposition; Respiratory distress; Risk; Role; Sampling; Sickle Cell; Tanzania; Testing; Thalassemia; Trust; Uganda; United States National Institutes of Health; Update; Vaccine Design; Vaccines; Variant; case control; comparative genomic hybridization; cost effective; data mining; density; design; disorder risk; genetic association; genome wide association study; immune function; insight; interest; killings; mortality; novel; novel strategies; population based; pressure; protective effect; research study

DESCRIPTION (provided by applicant): This is a PI-initiated, collaborative, case/control project to systematically identify human copy number polymorphisms (CNPs) that are associated with severe malaria anemia (SMA) and other forms of severe malaria. CNPs represent regions in the genome typically >1kb that differ in the number between normal individuals within the population and that occur in 1% or more of a given population. CNPs are enriched for genes with immune function and there are now a number CNPs associations that have been shown for infectious and autoimmune diseases. To date there has been no large scale study of CNPs for malaria, despite the fact that the extensive number of mutations cataloged affecting malaria still cannot account for the expected variation. We will use a collaboratively developed custom design for array comparative genomic hybridization (aCGH) that densely probes thousands of known CNPs within the human genome allowing us to accurately quantify their copy number and determine if they are associated with SMA. This project is designed to answer the question of whether CNPs account for a significant portion of the genetic variation that increase risk for SMA. To ensure that CNPs in our study populations are well represented, we will first conduct standard array comparative genomic hybridization discovery experiments. We will analyze 72 individuals, representing an equal number of cases and controls, using a commercially-available, high-density tiling microarray (4.2 million probes across the genome). This will identify CNPs within previously under- represented populations such as those found in East Africa that may have not been detected in studies of other human populations. We will then update our custom microarray with the latest set of known CNPs including the newly discovered CNPs. With this array we will type six thousand CNPs in SMA cases (800) and matched controls (800) from NIH and Welcome Trust/MalariaGen funded population-based studies of severe malaria. We will accurately determine CNP copy numbers in each individual and mine this data for associations between individual CNPs and disease status. The validity of these CNPs will be confirmed by replicate locus-specific testing in additional SMA cases and controls sample sets and the generalizability of these findings will be evaluated by testing additional DNA samples from patients with other forms of severe malaria (cerebral malaria and acute respiratory distress). The unique insights gained by this novel approach are expected to fill significant gaps in our understanding of human genetic susceptibility to malaria that will benefit malaria vaccine design strategies aiming to eradicate malaria from the globe.

描述（由申请人提供）：这是一个PI发起的协作病例/对照项目，旨在系统地鉴定与重度疟疾贫血（SMA）和其他形式的重度疟疾相关的人类拷贝数多态性（CNP）。CNP代表基因组中通常> 1 kb的区域，其在群体内的正常个体之间的数量不同，并且在给定群体的1%或更多中出现。CNP富含具有免疫功能的基因，现在已经显示出许多CNP与感染性和自身免疫性疾病相关。到目前为止，还没有大规模的疟疾CNP研究，尽管事实上，大量的突变编目影响疟疾仍然不能解释预期的变化。我们将使用一种合作开发的定制设计进行阵列比较基因组杂交（aCGH），该设计密集探测人类基因组中数千种已知的CNP，使我们能够准确定量其拷贝数并确定它们是否与SMA相关。该项目旨在回答CNP是否占增加SMA风险的遗传变异的重要部分的问题。为了确保我们研究人群中的CNPs得到充分代表，我们将首先进行标准阵列比较基因组杂交发现实验。我们将分析72个个体，代表相同数量的病例和对照，使用市售的高密度平铺微阵列（420万个探针横跨基因组）。这将在以前代表性不足的人群中识别CNP，例如在东非发现的那些可能在其他人群的研究中未检测到的CNP。然后，我们将用最新的一组已知的CNP（包括新发现的CNP）更新我们的自定义微阵列。有了这个阵列，我们将在来自NIH和Welcome Trust/MalariaGen资助的基于人群的严重疟疾研究的SMA病例（800例）和匹配对照（800例）中键入6000个CNP。我们将准确地确定每个个体中的CNP拷贝数，并挖掘这些数据以了解个体CNP与疾病状态之间的关联。将通过在额外SMA病例和对照样本集中进行重复基因座特异性检测来确认这些CNP的有效性，并将通过检测其他形式重度疟疾（脑型疟疾和急性呼吸窘迫）患者的额外DNA样本来评价这些结果的普遍性。通过这种新方法获得的独特见解有望填补我们对人类对疟疾遗传易感性的理解中的重大空白，这将有利于疟疾疫苗设计策略，旨在从地球仪上根除疟疾。