AGE, RACE, SEX AND AORTIC STIFFNESS--GENETIC MARKERS

年龄、种族、性别和主动脉僵硬——遗传标记

• 批准号: 2484287
• 负责人: FRANCOIS M BOOYSE
• 金额: $ 56.79万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2484287
• 关键词: age difference; angiocardioultrasonography; aorta; atherosclerosis; clinical research; disease /disorder proneness /risk; fibrinogen; fibrinolysis; gender difference; gene mutation; genetic markers; genotype; human subject; pathologic process; polymerase chain reaction; racial /ethnic difference; restriction fragment length polymorphism; statistics /biometry; vascular resistance

DESCRIPTION: (Adapted from Investigator's Abstract) Aging affects vascular cell function and arterial wall composition/structure which contributes to vascular stiffness and its underlying role as a risk factor for cardiovascular morbidity and mortality in the elderly. Age-related vascular stiffness is commensurate with a progressive increase in systolic blood pressure, atherosclerosis, matrix remodeling, CAD and eventual MI. Impaired blood fibrinolysis will initiate early fibrin deposition, atherogenesis, CAD, and CAD-associated vascular stiffness, resulting in atherothrombotic-occlusive events. CAD risk factors are associated with impaired blood fibrinolytic activity by altering the expression and/or activity of one or more of the fibrinolytic proteins. These proteins play an essential role in CAD-associated arterial matrix remodeling and consequentially also age-related CAD-associated vascular stiffness. The overall goal of this proposed study is to determine whether identification of specific genotypes or genotypic combinations of fibrinolytic proteins in conjunction with identifiable risk factors or risk factor-associated components (i.e., HTG-VLDL, Lp[a], insulin, homocysteine) may simultaneously identify categories of combined pathogenetic risk for atherosclerosis/CAD and age-related CAD-associated aortic stiffness. This case-control study will be carried out with a racial/gender mix of 1,640 subjects with angiographically identifiable CAD (>50% stenosis, 820 cases) and without CAD (normal coronary arteries) or CAD symptoms (820 controls). Specific studies will include the following: recruitment of cases/controls (Aim 1); identification of the mutation sites in the PA1-1 and u-PA genes to facilitate more cost-effective genotype analysis by PCR (Aim 2); determination of the amount/degree of aortic stiffness in all cases/controls, using Doppler ultrasound (pulse wave velocity) (Aim 3); determination of fibrinolytic protein genotypes (restriction fragment length polymorphisms, RFLPs) (Aim 4) and fibrinolytic protein antigen/activity, including Lp(a) and homocysteine levels, in case/control-derived blood samples (Aim 5); and finally, the multifactorial determination and statistical analysis of age-related CAD-associated aortic stiffness (Aim 6). The investigators state that the results gleaned from these studies will identify new fibrinolytic protein genotypes as mediators of environmental risk for CAD and further help to identify individuals at increased risk for age-related CAD-associated aortic stiffness, resulting in cardiovascular morbidity and mortality.

描述：（改编自研究者摘要）衰老影响血管 细胞功能和动脉壁组成/结构有助于 血管僵硬度及其作为危险因素的潜在作用 老年人心血管疾病的发病率和死亡率。 与年龄相关的血管 僵硬度与收缩压的逐渐增加相称 压力、动脉粥样硬化、基质重塑、CAD 和最终的 MI。 受损 血液纤维蛋白溶解将引发早期纤维蛋白沉积、动脉粥样硬化、 CAD 和 CAD 相关血管僵硬度，导致 动脉粥样硬化血栓闭塞事件。 CAD 风险因素与 通过改变表达和/或损害血液纤溶活性 一种或多种纤溶蛋白的活性。 这些蛋白质发挥着 在 CAD 相关动脉基质重塑中发挥重要作用 随之而来的还有与年龄相关的 CAD 相关血管僵硬。 这 这项研究的总体目标是确定识别是否 纤溶蛋白的特定基因型或基因型组合 与可识别的风险因素或与风险因素相关的 成分（即 HTG-VLDL、Lp[a]、胰岛素、同型半胱氨酸）可以同时 确定动脉粥样硬化/CAD 联合发病风险的类别 以及与年龄相关的 CAD 相关主动脉僵硬度。 这项病例对照研究 将对 1,640 名受试者进行种族/性别混合研究 血管造影可识别的 CAD（>50% 狭窄，820 例）且无 CAD （正常冠状动脉）或 CAD 症状（820 名对照）。 具体研究 将包括以下内容： 招募病例/对照（目标 1）； 鉴定 PA1-1 和 u-PA 基因中的突变位点 促进通过 PCR 进行更具成本效益的基因型分析（目标 2）； 确定所有患者的主动脉僵硬度的数量/程度 病例/对照，使用多普勒超声（脉搏波速度）（目标 3）； 纤溶蛋白基因型的测定（限制性片段长度 多态性、RFLP）（目标 4）和纤溶蛋白抗原/活性， 包括病例/对照血液中的 Lp(a) 和同型半胱氨酸水平 样品（目标 5）；最后，多因素决定和 与年龄相关的 CAD 相关主动脉僵硬度的统计分析（目标 6）。 研究人员表示，从这些研究中收集的结果将 鉴定新的纤溶蛋白基因型作为环境介质 CAD 风险，并进一步帮助识别患有 CAD 风险较高的个人 与年龄相关的 CAD 相关主动脉僵硬度，导致心血管疾病 发病率和死亡率。