Genetic Influences on Coronary Artery Calcification

遗传对冠状动脉钙化的影响

• 批准号: 7643207
• 负责人: BRAXTON D MITCHELL
• 金额: $ 71.73万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643207
• 关键词: Adult; American; Amish; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Biological; Biology; Blood Tests; Candidate Disease Gene; Cardiovascular Diseases; Caucasians; Caucasoid Race; Characteristics; Clinical; Communities; Complex; Coronary; Coronary Arteriosclerosis; Coupled; Detection; Disease; Disease susceptibility; Early Diagnosis; Elderly; Electron Beam; Enrollment; Environmental Risk Factor; Epidemiology; European; Event; Follow-Up Studies; Funding; Future; Gene Order; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Haplotypes; Health Care Costs; Human Genome; Image; Individual; Institutes; Knowledge; Left; Life Style; Linkage Disequilibrium; Maps; Measures; Methods; Minnesota; Molecular; Molecular Target; Nature; Patients; Persons; Phase; Phenotype; Population; Population Heterogeneity; Predisposition; Preventive Intervention; Quality of life; Research; Research Personnel; Risk; Role; Sample Size; Sampling; Sequence Analysis; Side; Signal Transduction; Single Nucleotide Polymorphism; Staging; Susceptibility Gene; Technology; Test Result; Testing; Variant; Work; base; calcification; cohort; coronary artery calcification; design; disorder risk; genetic linkage analysis; genome wide association study; insight; middle age; mortality; novel therapeutic intervention; programs

DESCRIPTION (provided by applicant): The overall objective of this proposal is to identify genes that influence susceptibility to cardiovascular disease through their influence on levels of coronary artery calcification (CAC). The presence and quantity of CAC predicts risk of future CVD events and levels of CAC are highly heritable. This proposal takes advantage of two large cohorts of individuals who have been phenotyped for CAC using EBCT technology and recent advances in genomics that make feasible the identification of disease susceptibility genes through genome-wide association (GWA) approaches. We hypothesize that genes influencing variation in CAC will be readily identified through GWA analysis with densely spaced SNPs. To test this hypothesis, we will carry out a 2-stage design in which we will first screen 800 Amish subjects using a GWA scan (Stage I), and then genotype associated SNPs in a second (Stage II) population of European Caucasian ancestry individuals from Rochester, MN from the Epidemiology of Coronary Artery Calcification Study. The Amish are a particular advantageous population to carry out such studies because of their common genetic ancestry and homogenous lifestyle. Through previous work, we have measured CAC in 800 Amish adults, in whom we are currently genotyping 500K Affymetrix SNP chips as part of other studies. In Specific Aim 1, we will genotype the remaining 300 subjects and carry out a GWA analysis of CAC. In Specific 2, we will identify the 1,750 most significantly associated SNPs from Stage 1 (representing 0.35% of the total number of SNPs tested) and will genotype these, as well as two flanking SNPs for each, in 900 subjects from the ECAC Study. Following these analyses, we will (as Specific Aim 3), prioritize the most compelling positional candidate genes and perform exhaustive analysis for sequence variation followed by association analysis to identify the most likely causative SNPs/haplotypes. Discovery of CAC susceptibility genes will provide: (i) critical insights into molecular mechanisms; (ii) new targets for therapy; (ii) blood tests for early detection of at risk persons so that preventive interventions can be instituted. This will impact substantially on mortality, quality of life, and health care costs for millions of middle-aged and elderly Americans.

描述（由申请人提供）：该提案的总体目标是通过影响冠状动脉钙化（CAC）水平来识别影响心血管疾病易感性的基因。 CAC 的存在和数量可预测未来 CVD 事件的风险，并且 CAC 水平具有高度遗传性。该提案利用了利用 EBCT 技术对 CAC 进行表型分析的两大个体群体以及基因组学的最新进展，使得通过全基因组关联 (GWA) 方法鉴定疾病易感基因成为可能。我们假设通过密集 SNP 的 GWA 分析可以很容易地识别影响 CAC 变异的基因。为了检验这一假设，我们将进行两阶段设计，首先使用 GWA 扫描筛选 800 名阿米什受试者（第一阶段），然后在欧洲白种人血统个体的第二个群体（第二阶段）中对相关 SNP 进行基因分型来自明尼苏达州罗彻斯特的冠状动脉钙化流行病学研究。阿米什人是进行此类研究的特别有利的人群，因为他们有共同的遗传血统和同质的生活方式。通过之前的工作，我们测量了 800 名阿米什成年人的 CAC，作为其他研究的一部分，我们目前正在对他们的 500K Affymetrix SNP 芯片进行基因分型。在具体目标 1 中，我们将对剩余 300 名受试者进行基因分型，并对 CAC 进行 GWA 分析。在具体 2 中，我们将确定第 1 阶段中 1,750 个最显着相关的 SNP（占测试 SNP 总数的 0.35%），并对来自 ECAC 研究的 900 名受试者的这些以及每个 SNP 的两个侧翼 SNP 进行基因分型。在这些分析之后，我们将（作为具体目标 3）优先考虑最引人注目的位置候选基因，并对序列变异进行详尽的分析，然后进行关联分析，以确定最可能的致病 SNP/单倍型。 CAC 易感基因的发现将提供：(i) 对分子机制的重要见解； (ii) 新的治疗目标； (ii) 血液检测以及早发现高危人群，以便采取预防性干预措施。这将对数百万美国中老年人的死亡率、生活质量和医疗保健费用产生重大影响。