Copy Number Variants (CNVs) and Subclinical Atherosclerosis in MESA

描述（由申请人提供）：本申请涉及广泛挑战领域（08）：基因组学和特定挑战主题，08- hl -104：评估非裔美国人的遗传变异并确定其对疾病的影响。冠状动脉疾病（CAD）是世界范围内死亡的主要原因，也是美国最大的杀手。本研究的目的是确定基因组结构变异（例如拷贝数变异，CNVs）在亚临床心血管疾病（CVD）风险中的作用。本申请提出了“MESA CNV”辅助研究，以确定非大多数人群中冠状动脉钙（CAC），颈动脉壁厚度（IMT）和危险因素（HDL， LDL）变异的遗传贡献程度。虽然有一些研究调查了冠状动脉钙化、亚临床动脉粥样硬化和危险因素的遗传学，但绝大多数研究涉及高加索人群的SNP基因分型。目前的建议是独特的，因为它结合了亚临床动脉粥样硬化的多种测量方法，并强调了非大多数美国种族和家庭以及结构遗传变异的作用。利用MESA家族研究的资源，我们建议验证CNVs位于基因组的选定区域并将有助于动脉粥样硬化的遗传风险的假设。此外，cnv的一个子集可能存在于现有GWAS研究已经确定的区域，因此，增加了候选基因在调控中具有特定功能的可能性，从而确定了潜在的治疗靶点。重要的是要针对整个基因组来识别潜在的cnv影响的动脉粥样硬化风险位点。本项目拟对可能改变动脉粥样硬化风险并影响其相关表型和危险因素的结构变异（CNVs）进行基因组评估。一些已知的CNVs位于通过连锁和关联扫描确定的现有CVD易感性区域附近。该项目本身将为精细定位、基因作用和功能提供重要线索。该项目是全面的，因为它针对全基因组的CNVs对动脉粥样硬化风险的影响。该研究在利用MESA非洲裔美国人和西班牙裔家庭的独特资源进行基因分型方面具有高度创新性，并建议进行全面的制图和分析，以确定区域位置、基因鉴定和与结构变异相关的潜在因果变异。本研究将由两部分组成，常见CNVs的评估和罕见CNVs对动脉粥样硬化风险的检测。共同CNV分析将利用了解人类结构变异的最新进展，结合使用家族数据的强大实验设计，扩展可用于CVD/动脉粥样硬化关联测试的共同CNV集。家庭的大样本量也将提供前所未有的统计能力，以确定与常见CNVs的新关联。罕见CNV分析将调查一组迄今未被关联研究发现的遗传变异：罕见变异（在队列中，小等位基因频率低至0.5%），但对疾病风险有强烈影响（优势比在2-3范围内）。由于这些强大的影响，这些相关的罕见变异将成为未来功能研究的杰出候选者，旨在提高我们对病因的理解。本研究将极大地推动心血管疾病和动脉粥样硬化遗传基础的研究，并为今后的功能研究奠定基础。作为MESA研究（和MESA SHARe）的一部分，这些数据将与预期的MESA全基因组关联扫描结合使用整个基因组的snp。此外，与NHLBI关于全基因组研究的规定一致，所有数据将被存储供更大的科学界使用，并可通过dbGaP访问。该项目是MESA和MESA家庭研究调查人员对数据进行研究的延伸，只有通过这种合作努力才能实现。动脉粥样硬化是一种复杂的自身免疫性疾病，由多种遗传和环境风险因素的作用引起，通过其在临床重大事件（心脏病、中风）和发病率/死亡率增加中的作用，对美国公众健康造成了重大负担。本研究提出扫描人类基因组，以识别与动脉粥样硬化风险相关的结构变异（拷贝数变异，CNVs）。确定动脉粥样硬化的遗传危险因素是进行风险预测、干预和开发预防治疗的第一步。

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area (08): Genomics and specific Challenge Topic, 08-HL-104: Assess Genetic Variation in African Americans and determine its effect on disease. Coronary artery disease (CAD) is a leading cause of death worldwide and the largest killer in the United States. The goal of this study is to determine the role of structural variation in the genome (e.g., copy number variants, CNVs) contributing to subclinical cardiovascular disease (CVD) risk. This application proposes the "MESA CNV" ancillary study to determine the extent of genetic contribution to variation in coronary artery calcium (CAC), carotid artery wall thickness (IMT), and risk factors (HDL, LDL) in non- majority populations. While there are some studies investigating the genetics of coronary calcification, subclinical atherosclerosis and risk factors, the vast majority of studies involve SNP genotyping in Caucasian populations. The current proposal is unique for its combination of multiple measures of subclinical atherosclerosis and in its emphasis on non-majority U.S. ethnic groups and families and the role of structural genetic variants. Using the resources of the MESA Family Study, we propose to test the hypothesis that CNVs are located in selected regions of the genome and will contribute to the genetic risk for atherosclerosis. Further, a subset of the CNVs may reside in regions already identified by the existing GWAS studies and, therefore, increase the likelihood that the candidate gene may have a specific function in regulation, thereby identifying potential therapeutic targets. It is important to target the entire genome to identify potential CNV-influenced atherosclerosis risk loci. This project proposes to perform genomic evaluation of structural variants (CNVs) that may modify risk for atherosclerosis and have effects on its correlated phenotypes and risk factors. Some known CNVs are located near existing CVD susceptibility regions identified by linkage and association scans. This project will, in itself, provide important clues for fine mapping, gene action and function. The project is comprehensive, as it targets the entire genome for implication of CNVs on risk in atherosclerosis. It is highly innovative in its use of a unique resource of MESA African-American and Hispanic families previously genotyped, and proposes to perform comprehensive mapping and analysis to identify regional location, gene identification, and potential causal variant(s) associated with structural variation. This study will consist of two components, evaluation of common CNVs and detection of rare CNVs on atherosclerosis risk. The common CNV analysis will take advantage of the latest advances in the understanding human structural variation, combined with a powerful experimental design using family data, to extend the set of common CNVs that can be tested for CVD/atherosclerosis association. The large sample size of families will also provide an unprecedented statistical power to identify new associations with common CNVs. The rare CNV analysis will investigate a set of genetic variants so far unexplored by association studies: rare variants (minor allele frequency as low as 0.5% in the cohort) but with strong effects on disease risk (odds ratio in the 2-3 range). Owing to these strong effects, such associated rare variants will be outstanding candidates for future functional studies designed to improve our understanding of etiology. The proposed research will greatly advance the field of CVD and genetic basis of atherosclerosis and will provide a foundation for future functional studies. As part of the MESA Study (and MESA SHARe), these data will be coupled with the anticipated MESA genome-wide association scan using SNPs throughout the genome. In addition, consistent with the NHLBI regulations on genome-wide studies, all data will be deposited for use by the greater scientific community and will be accessible through dbGaP. The project represents an extension of the research performed to data by the MESA and MESA Family Study investigators and will be possible only through this collaborative effort. Atherosclerosis is a complex autoimmune disorder that arises from the action of multiple genetic and environmental risk factors with significant burden to the public health of the United States through its role in clinically significant events (heart disease, stroke) and increased morbidity/mortality. This research proposes to scan the human genome in order to identify structural variants (copy number variants, CNVs) that are associated with risk of atherosclerosis. Identification of genetic risk factors for atherosclerosis is the first step in risk prediction, intervention and developing therapeutics for prevention.