AGE, RACE, VASCULAR STIFFNESS: GENETIC MARKERS

年龄、种族、血管僵硬：遗传标记

• 批准号: 6263441
• 负责人: FRANCOIS M BOOYSE
• 金额: $ 2.95万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6263441
• 关键词: aging; atherosclerosis; clinical research; coronary disorder; disease /disorder proneness /risk; ethnic group; fibrinolysis; gene mutation; genetic mapping; genetic markers; genotype; human subject; polymerase chain reaction; racial /ethnic difference; restriction fragment length polymorphism; ultrasound blood flow measurement; vascular resistance

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 evential MI. Impaired blood fibrinolysis will initiate early fibrin deposition, atherogenesis, CAD, CAD-associated vascular stiffness, resulting in atherothrombotic-occlusive events. CAD risk factors (i.e. obesity, diabetes, hypertension, hypertriglyceridemia [HTG], increased Lp(a)/homocysteine/fibrinogen), are associated with impaired blood fibrinolytic activity by altering the expression and/or activity of one or more of the fibrinolytic proteins, PAI-1, t-PA and u-PA. In addition, key multiallelic fibrinolytic proteins (PAI-1, t-PA, u-PA, including '-fibrinogen) play an essential role in CAD-associated arterial matrix remodeling and consequencially 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 (see above), 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 (350% stenosis)(820 cases) and without CAD (normal coronary arteries) or CAD symptoms (820 controls). Specific studies will include: recruitment of cases/controls) (Aim I); identification of the mutation sites in the PAI-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).

衰老影响血管细胞功能和动脉壁组成/结构，导致血管僵硬及其作为老年人心血管发病率和死亡率风险因素的潜在作用。动脉粥样硬化相关的血管僵硬度与收缩压、动脉粥样硬化、基质重塑、CAD和事件性MI的进行性增加相称。 血纤维蛋白溶解受损会引发早期纤维蛋白沉积、动脉粥样硬化形成、CAD、CAD相关血管僵硬，导致动脉粥样硬化血栓闭塞性事件。 CAD风险因素（即肥胖、糖尿病、高血压、高脂血症[HTG]、增加的Lp（a）/高半胱氨酸/纤维蛋白原）通过改变纤溶蛋白PAI-1、t-PA和u-PA中的一种或多种的表达和/或活性而与受损的血液纤溶活性相关。 此外，关键的多等位基因纤溶蛋白（PAI-1，t-PA，u-PA，包括'-纤维蛋白原）在CAD相关的动脉基质重塑中起重要作用，因此也与年龄相关的CAD相关的血管僵硬。 这项拟议研究的总体目标是确定纤溶蛋白（见上文）的特定基因型或基因型组合的鉴定，以及可识别的风险因素或风险因素相关组分（即HTG-VLDL、Lp [a]、胰岛素、同型半胱氨酸）是否可以同时识别动脉粥样硬化/CAD和年龄相关CAD相关主动脉僵硬的联合发病风险类别。 本病例对照研究将在1，640例具有血管造影可识别的CAD（350%狭窄）（820例病例）和无CAD（正常冠状动脉）或CAD症状（820例对照）的受试者中进行。 具体研究将包括：招募病例/对照组）（目的I）;通过PCR鉴定PAI-1和u-PA基因中的突变位点，以促进更具成本效益的基因型分析（目的2）;使用多普勒超声确定所有病例/对照组中主动脉僵硬的数量/程度脉搏波传导速度（Aim 3）;纤溶蛋白基因型测定（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/对照来源的血液样本中的Lp（a）和同型半胱氨酸水平（目标5）;最后，年龄相关CAD相关主动脉僵硬度的多因素测定和统计分析（目标6）。