PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

这一竞争性更新提案（06-10年级）的总体目标仍然是 与最初的补助金（01-05年）相同;即， 影响动脉粥样硬化病变范围和严重程度的因素 年轻人的尸体解剖 这个基因工程是两个组成部分 全国性多中心研究，收集和测量 来自事故、凶杀和自杀受害者的动脉组织（年龄 15-34）。 最初的多中心研究被命名为“病理生物学 青年动脉粥样硬化的决定因素（PDAY）”，并收集了 1，532例来自8个法医病理学实验室， 国家 为了获得更多的病例（特别是女性），PDAY 在一个名为“早期人类的危险因素”的项目中继续收集数据。 动脉粥样硬化（RFEHA）。“PDAY-RFEHA病例总数为 预计为2654人。 PDAY-RFEHA研究还测量了已知风险 动脉粥样硬化疾病的因素，包括死后血清水平 脂质和脂蛋白，硫氰酸盐（吸烟的措施），和 糖化血红蛋白（糖尿病的衡量标准）。 其他测量 包括肾小动脉医学厚度（测量高血压） 和皮下脂肪（肥胖的测量）。 1988年PDAY遗传研究开始于收集肝脏样本（50 g） 从每个案件。 每种样品的一小部分（0.5 g）用于 提取DNA，其余部分储存在-80摄氏度作为国家 为未来的遗传学研究提供资源。 肝脏DNA用于 确定候选基因中多态性的基因型， 动脉粥样硬化 基因型用于统计和人口 基因分析，以确定其对测量的风险因素的影响， 动脉病变 PDAY基因研究的独特之处在于， 识别影响病变的基因，即使在没有测量的情况下， 生理中间体 在0-1-05年，该项目的重点是 参与胆固醇代谢的基因（载脂蛋白和LDL 受体），导致首次发表的报告的影响， 基因多态性对动脉粥样硬化的直接测量。 多年来 06-10，我们建议继续我们的基因研究， 胆固醇代谢，并开始开始一项新的倡议，检查影响 直接参与动脉壁损伤的基因。 本竞争性续约提案的目的是（1）继续 采集PDAY-RFEHA肝脏样本并提取DNA，以增加 用于统计分析的病例数（特别是女性），（2） 继续进行脂质代谢相关基因的分型，（3）鉴定和 动脉壁病变相关基因的多态性，（4） 应用不依赖于限制差异的新技术 酶切位点检测多态性，（5）进行统计学分析 和群体遗传分析，以确定候选基因的影响， 多态性对测量的风险因素和程度和严重性 动脉粥样硬化，和（6）确定潜在的核苷酸序列 基因型关联的差异。

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.