PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

青年动脉粥样硬化的病理学决定因素

• 批准号: 3356878
• 负责人: JAMES E. HIXSON
• 金额: $ 16.18万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3356878
• 关键词: adolescence (12-20); apolipoproteins; atherosclerosis; blood lipid; blood pressure; cholesterol; diabetes mellitus; disease /disorder proneness /risk; gene expression; genetic markers; genetic polymorphism; genotype; human genetic material tag; human tissue; low density lipoprotein; molecular pathology; nucleic acid probes; obesity; polymerase chain reaction; postmortem; southern blotting; tobacco abuse; young adult human (21-34)

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.

该竞争性更新提案（YRS 06-10）的总体目标仍然存在 与原始赠款相同（YRS 01-05）；也就是说，识别遗传 影响动脉粥样硬化病变程度和严重程度的因素 在尸检年轻人中。 这个遗传项目是两个的组成 全国多中心研究，收集和测量病变 事故，凶杀和自杀受害者的动脉组织（年龄 15-34）。 最初的多中心研究标题为“病理生物学 青年动脉粥样硬化的决定因素（pday），并收集了总计 整个八个法医病理实验室的1,532例 国家。 为了获得其他病例（尤其是女性），pday 在一个标题为“早期人类的风险因素的项目中，都继续收集 动脉粥样硬化（RFEHA）。 预计为2,654。 Pday-rfeha研究还衡量已知风险 动脉粥样硬化疾病的因素，包括验尸血清水平 脂质和脂蛋白，硫氰酸酯（吸烟的量度）和 糖基化血红蛋白（糖尿病的量度）。 其他测量 包括肾动脉的医学厚度（高血压量度） 和皮下脂肪（肥胖症的量度）。 1988年的Pday遗传研究始于收集肝样品（50 g） 从每种情况下。 每个样品的一小部分（0.5 g）用于 提取DNA，其余部分存储在-80度C作为国家 未来遗传研究的资源。 肝DNA习惯 确定候选基因多态性的基因型 动脉粥样硬化。 基因型用于统计和人群 遗传分析以确定其对测得的风险因素的影响和 动脉病变。 Pday遗传研究的能力是独一无二的 识别影响病变的基因，即使没有测量 生理中间体。 在05年1月，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），导致有关影响的首次发布的报告 直接测量动脉粥样硬化的遗传多态性。 在几年中 06-10，我们建议继续我们对涉及的基因的研究 胆固醇代谢，并开始一项新计划以检查影响 直接参与动脉壁病变的基因。 该竞争性更新建议的目的是（1）继续 pday-rfeha肝样品的获取和提取DNA以增加 用于统计分析的病例数（特别是女性），（2） 继续键入涉及脂质代谢的基因，（3）识别和 在动脉壁中涉及病变的基因中的类型多态性，（4） 应用不依赖限制差异的新技术 酶切割位点检测多态性，（5）执行统计 和种群遗传分析以确定候选基因的影响 对测得的风险因素以及程度和严重程度的多态性 动脉粥样硬化，（6）确定潜在的核苷酸序列 负责基因型关联的差异。