Genetic Influences on Coronary Artery Calcification

遗传对冠状动脉钙化的影响

基本信息

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
项目类别：
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

项目摘要

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）：该提案的总体目的是通过影响其对冠状动脉钙化水平（CAC）的影响来识别影响心血管疾病易感性的基因。 CAC的存在和数量可以预测未来CVD事件和CAC水平的风险是高度遗传的。该提案利用了两个大型人群，他们使用EBCT技术和基因组学的最新进展进行了表型，这些人通过基因组全基因组关联（GWA）方法可行地识别疾病易感基因。我们假设，通过密集间隔的SNP，可以通过GWA分析很容易地识别影响CAC变异的基因。为了检验这一假设，我们将进行2阶段的设计，在该设计中，我们将使用GWA扫描（I期）筛选800名Amish受试者，然后在第二个（II期）（II期）欧洲高加索祖先的基因型中与SNP相关的SNP，来自明尼苏达州罗切斯特，来自明尼苏达州罗切斯特，来自明尼苏达州的冠状动脉钙化研究。阿米什人是一个特别有利的人群，因为它们具有共同的遗传血统和同质生活方式，因此进行了此类研究。通过先前的工作，我们已经测量了800名阿米什人成年人的CAC，目前我们正在基因分型为500K Affymetrix SNP芯片，作为其他研究的一部分。在特定的目标1中，我们将基因类型的剩余300名受试者进行基因型，并对CAC进行GWA分析。在特定2中，我们将在第1阶段确定1,750个最显着相关的SNP（代表了测试的SNP总数的0.35％），并将在ECAC研究中的900名受试者中，每个受试者的基因型以及两个侧翼SNP。按照这些分析，我们将（作为特定目标3）优先考虑最引人注目的位置候选基因，并对序列变化进行详尽的分析，然后进行关联分析，以识别最可能的原因SNP/单倍型。发现CAC敏感性基因将提供：（i）对分子机制的关键见解；（ii）治疗的新目标；（ii）早期发现AT风险人员的血液测试，以便进行预防性干预措施。这将对数百万中年和老年美国人的死亡率，生活质量和医疗费用产生重大影响。