Role of gamma' Fibrinogen in Cardiovascular Disease

描述(申请人提供)：血浆纤维蛋白原水平升高，这是血液凝块的主要结构蛋白，与心血管疾病密切相关。但是，尽管纤维蛋白原满足许多病因学标准，但目前尚不清楚纤维蛋白原水平升高是心血管疾病的重要原因还是其影响。纤维蛋白原与心血管疾病之间的这种联系可能不仅在于血浆纤维蛋白原水平，还在于其组成。我们发现，一种称为Gamma Prime(GammaA/Gamma‘)的次要纤维蛋白原亚型水平升高与冠状动脉疾病有关。这一观察结果与一个独立研究小组的研究结果一致，该研究小组报告了伽马A/伽马‘纤维蛋白原与总纤维蛋白原的比率与动脉血栓形成之间的关系。然而，到目前为止，还没有研究直接测试GammaA/Gamma‘纤维蛋白原与传统心血管疾病风险因素(如吸烟、高血压、糖尿病和胆固醇)之间的关系。此外，GammaA/Gamma‘纤维蛋白原的临床和生化特性表明，它直接参与心血管疾病的发病机制。在本申请中，我们提出了三个具体目标： 1)确定GammaA/GammaA纤维蛋白原和GammaA/GammaA纤维蛋白原在Framingham子代队列中的分布，并调查性别和年龄特征。 2)确定纤维蛋白原亚型与已建立的心血管疾病危险因素之间的关系。 3)确定血浆纤维蛋白原异构体是否与CVD独立相关。

DESCRIPTION (provided by applicant): Elevated levels of plasma fibrinogen, the major structural protein of blood clots, are strongly associated with cardiovascular disease. But while fibrinogen fulfills many etiological criteria, it remains unclear whether elevated levels of fibrinogen are an important cause of cardiovascular disease or an effect of it. This link between fibrinogen and cardiovascular disease may lie not only in the level of plasma fibrinogen, but also in its composition. We found that elevated levels of a minor fibrinogen isoform called gamma prime (gammaA/gamma') fibrinogen were associated with coronary artery disease. This observation is consistent with findings from an independent research group, who reported an association between the ratio of gammaA/gamma' fibrinogen to total fibrinogen and arterial thrombosis. To date, however, no study has directly tested the association between gammaA/gamma' fibrinogen and traditional cardiovascular disease risk factors (e.g. smoking, hypertension, diabetes, and cholesterol). Furthermore, the clinical and biochemical properties of gammaA/gamma' fibrinogen implicate it in direct mediation of cardiovascular disease pathogenesis. In this application, we propose three Specific Aims: 1) To determine the distribution of gammaA/gammaA fibrinogen and gammaAgamma' fibrinogen among the Framingham Offspring cohort and investigate gender- and age-specific characteristics. 2) To determine the relationship between fibrinogen isoforms and established cardiovascular disease risk factors. 3) To determine if the fibrinogen isoforms in plasma are independently associated with CVD.