AGE, RACE, VASCULAR STIFFNESS: GENETIC MARKERS

衰老影响血管细胞功能和动脉壁组成/结构，从而导致血管僵硬，并成为老年人心血管发病率和死亡率的潜在危险因素。与年龄相关的血管僵硬与收缩压、动脉粥样硬化、基质重构、冠心病和事件心肌梗死的进行性增加是相称的。血液纤溶受损会引发早期纤维蛋白沉积、动脉粥样硬化、冠心病、冠心病相关血管僵硬，导致动脉粥样硬化-血栓闭塞事件。冠心病危险因素(如肥胖、糖尿病、高血压、高甘油三酯血症、Lp(A)/同型半胱氨酸/纤维蛋白原升高)通过改变纤溶蛋白PAI-1、t-PA和u-PA中的一个或多个的表达和/或活性，与血液纤溶活性受损有关。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)在冠心病相关的动脉基质重塑以及随后与年龄相关的血管僵硬中起着重要作用。这项拟议研究的总体目标是确定确定特定的基因类型或纤溶蛋白的基因组合(见上文)，以及可识别的风险因素或风险因素相关成分(即HTG-VLDL、Lp[a]、胰岛素、同型半胱氨酸)是否可以同时确定动脉粥样硬化/冠心病和年龄相关的CAD相关主动脉僵硬的联合致病风险类别。这项病例对照研究将对1640名经血管造影可识别的冠心病(350%狭窄)(820例)和没有冠心病(冠状动脉正常)或冠心病症状(820名对照)的受试者进行种族/性别混合。具体研究将包括：招募病例/对照(目标一)；确定PAI-1和u-PA基因的突变位置，以便于通过聚合酶链式反应进行更具成本效益的基因分析(目标2)；利用多普勒超声(脉搏波速)确定所有病例/对照的主动脉僵硬的数量/程度(目标3)；确定纤溶蛋白基因类型(限制性片段长度多态，RFLP)(目标4)和纤溶蛋白抗原/活性，包括Lp(A)和来自病例/对照的血液样本中的同型半胱氨酸水平(目标5)；最后，对与年龄相关的冠心病相关的主动脉僵硬进行多因素测定和统计分析(目标6)。

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).