PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

这项竞争性续签提案(2006年至2010年)的总体目标仍然是 与最初的赠款相同(01-05年)；即识别基因 影响动脉粥样硬化病变范围和严重程度的因素 在身体解剖的年轻人身上。这个基因工程是两个基因工程的组成部分 全国范围内的多中心研究，收集和测量 事故、凶杀和自杀受害者的动脉组织(年龄 15-34)。最初的多中心研究名为《病理生物学》 青年动脉粥样硬化的决定因素(PDAY)，并收集了 来自全国8个法医病理实验室的1,532例病例 国家。为了获得更多病例(特别是女性)，PDAY 收集工作在一个名为《早期人类的风险因素》的项目中继续进行 动脉粥样硬化(RFEHA)。 预计为2654人。PDAY-RFEHA研究也衡量了已知风险 动脉粥样硬化性疾病的因素，包括死后血清水平 脂类和脂蛋白、硫氰酸盐(吸烟的衡量标准)和 糖化血红蛋白(糖尿病的衡量标准)。其他量度 包括肾小动脉的医学厚度(高血压的衡量标准) 和皮下脂肪(肥胖的衡量标准)。 1988年的PDAY遗传学研究开始于收集肝脏样本(50克) 从每一个案例中。每个样品的一小部分(0.5g)用于 提取DNA，其余部分保存在零下80℃作为国家 为未来的基因研究提供资源。肝脏DNA被用来 确定候选基因的多态类型 动脉硬化。基因分型用于统计和人口统计 基因分析，以确定它们对测量的风险因素和 动脉损伤。PDAY基因研究的独特之处在于它能够 识别影响损伤的基因，即使在没有测量的情况下也是如此 生理中间体。在0-1-05年，本项目重点关注 与胆固醇代谢有关的基因(载脂蛋白和低密度脂蛋白 受体)，导致了第一批发表的关于 直接测量动脉粥样硬化的遗传多态。以年为单位 06-10，我们建议继续研究涉及 胆固醇代谢，并开始一项新的倡议，以检查影响 与动脉壁损伤直接相关的基因。 这项竞争性续签提案的目的是(1)继续 PDAY-RFEHA肝脏标本的获取及DNA提取 用于统计分析的病例数量(特别是女性)，(2) 继续对涉及脂类代谢的基因进行分型，(3)确定和 动脉壁病变相关基因的类型多态，(4) 应用不依赖于限制差异的新技术 酶裂解位点检测多态，(5)进行统计 和群体遗传分析以确定候选基因的效应 测量的危险因素和程度和严重程度的多态 动脉粥样硬化，以及(6)确定潜在的核苷酸序列 导致基因关联的差异。

The overall goal of this competitive renewal proposal (yrs 06-10) remains the same as the original grant (yrs 01-05); that is, to identify genetic factors that influence the extent and severity of atherosclerotic lesions in autopsied young persons. This genetic project is a component of two nationwide multicenter studies that collect and measure lesions in arterial tissues from victims of accidents, homicide, and suicide (ages 15-34). The initial multicenter study was entitled "Pathobiological Determinants of Atherosclerosis in Youth (PDAY)," and collected a total of 1,532 cases from eight forensic pathology laboratories throughout the country. To obtain additional cases (particularly females), the PDAY collection was continued in a project titled "Risk Factors of Early Human Atherosclerosis (RFEHA)." The total number of PDAY-RFEHA cases is projected to be 2,654. PDAY-RFEHA studies also measure known risk factors of atherosclerotic diseases, including postmortem serum levels of lipids and lipoproteins, thiocyanate (measure of smoking), and glycosylated hemoglobin (measure of diabetes). Other measurements include medical thickness of renal arterioles (measure of hypertension) and subcutaneous fat (measure of obesity). The 1988 PDAY genetic study began by collection of liver samples (50 g) from each case. A small portion of each sample (0.5 g) is used to extract DNA, and the remainder is stored at -80 degrees C as a national resource for future genetic studies. The hepatic DNA is used to determine genotypes for polymorphisms in candidate genes of atherosclerosis. The genotypes are used for statistical and population genetic analyses to determine their effects on measured risk factors and arterial lesions. The PDAY genetic study is unique in its ability to identify genes that affect lesions, even in the absence of measured physiological intermediates. In years 0-1-05, this project focused on genes involved in cholesterol metabolism (apolipoproteins and the LDL receptor), resulting in the first published reports of the effects of genetic polymorphisms on direct measures of atherosclerosis. In years 06-10, we propose to continue our studies of genes involved in cholesterol metabolism, and to begin a new initiative to examine effects of genes that are directly involved in lesions in the arterial wall. The aims of this competitive renewal proposal are to (1) continue acquisition of PDAY-RFEHA liver samples and extraction of DNA to increase numbers of cases (particularly females) for statistical analyses, (2) continue typing of genes involved in lipid metabolism, (3) identify and type polymorphisms in genes involved in lesions in the arterial wall, (4) apply new techniques that do not rely on differences in restriction enzyme cleavage sites to detect polymorphisms, (5) perform statistical and population genetic analyses to determine effects of candidate gene polymorphisms on measured risk factors and extent and severity of atherosclerosis, and (6) determine the underlying nucleotide sequence differences that are responsible for genotype associations.