GENCAC - North Carolina Field Center

GENCAC - 北卡罗来纳州现场中心

• 批准号: 6527758
• 负责人: Lynne E Wagenknecht
• 金额: $ 37.85万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-17 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527758
• 关键词: African American; aorta disorder; atherosclerosis; calcification; cardiovascular disorder epidemiology; clinical research; cooperative study; coronary disorder; family genetics; gene environment interaction; genetic polymorphism; genetic screening; genetic susceptibility; human genetic material tag; human subject; inflammation

The purpose of the proposed study, Genetics of Coronary and Aortic Calcification (GENCAC), is to identify genetic factors that establish susceptibility to (a) coronary and aortic atherosclerosis and (b) inter- individual variability in the inflammatory response. We propose to quantify coronary and aortic artery calcium volume in 441 selected, informative pedigrees (--3,000 individuals) previously examined and extensively genotyped (-400 markers spanning the genome) by the NHLBI Family Heart Study, in order to identify genes associated with human atherosclerosis. An additional 275 African American sibships (- 600 individuals, also examined and comparably genotyped) will be included to address these study questions in this high-risk population. Assessment of the inter-individual variability in the inflammatory burden and the host response, and the extensive metabolic, behavioral, and environmental data already collected on these pedigrees will provide enhanced phenotypic homogeneity and increased analytic power in assessing the genetic basis of atherosclerosis. State of the art laboratory and statistical methods will be used to find, localize and characterize the influence of predisposing genes to atherosclerosis and the inflammatory response. Novel genetic analysis methods will be used to address the issues of phenotypic, genetic and population heterogeneity, epistasis, complex interactions among the genetic and environmental risk factors, and to optimize the detection of genomic regions affecting phenotypic susceptibility. The notorious issue of multiple comparisons in genome scans will be bypassed with the use of novel global testing procedures. Based on a cost-efficient design of informative pedigrees and employing novel methodology, this study will contribute currently unavailable information on genetic and environmental determinants of atherosclerosis, with a focus on the prevention of this widely prevalent condition associated with high burden of costs to society. This application corresponds to the GENCAC clinic submitted by the Wake Forest University School of Medicine as part of the GENCAC genetic epidemiology network.

拟议的研究“冠状动脉和主动脉钙化遗传学（GENCAC）”的目的是确定对（a）冠状动脉和主动脉粥样硬化以及（b）炎症反应的个体差异易感性的遗传因素。我们建议量化 441 个选定的、信息丰富的谱系（-3,000 个人）的冠状动脉和主动脉钙量，这些谱系先前由 NHLBI 家庭心脏研究进行了检查和广泛的基因分型（跨越基因组的 -400 个标记），以便识别与人类动脉粥样硬化相关的基因。另外 275 名非裔美国人同胞（600 名个体，也进行了检查和比较基因分型）将被纳入其中，以解决这一高风险人群中的这些研究问题。对炎症负担和宿主反应的个体间变异性的评估，以及在这些谱系中已经收集的广泛代谢、行为和环境数据，将增强表型同质性，并增强评估动脉粥样硬化遗传基础的分析能力。最先进的实验室和统计方法将用于发现、定位和表征易感基因对动脉粥样硬化和炎症反应的影响。新的遗传分析方法将用于解决表型、遗传和群体异质性、上位性、遗传和环境风险因素之间复杂的相互作用等问题，并优化影响表型易感性的基因组区域的检测。通过使用新颖的全球测试程序，可以绕过基因组扫描中的多重比较这一臭名昭著的问题。基于信息谱系的成本效益设计并采用新颖的方法，这项研究将提供目前无法获得的关于动脉粥样硬化的遗传和环境决定因素的信息，重点是预防这种广泛流行的疾病，并给社会带来高昂的费用负担。该应用程序对应于维克森林大学医学院提交的 GENCAC 诊所，作为 GENCAC 遗传流行病学网络的一部分。