Genome-wide Association Study for Gamma' Fibrinogen Expression

描述(由申请人提供)：这项申请的长期目标是阐明‘纤维蛋白原异构体的基因调控，作为了解其在心血管疾病中的作用的基础。这项拟议的研究背后的具体假设是，这一假设被提升了吗？根据几项观察，纤维蛋白原水平会导致心血管疾病。首先，纯净吗？纤维蛋白原在体外形成凝块，其机械硬度比普通纤维蛋白原高。其次，提纯的纤维蛋白原形成纤维蛋白凝块，可抵抗纤溶。第三，减少了吗？纤维蛋白原水平与静脉血栓形成和血栓性微血管病变相关。第四，高高在上？正如斯德哥尔摩冠状动脉疾病风险因素研究和弗雷明翰心脏研究显示的那样，纤维蛋白原水平与动脉心血管疾病密切相关，与总纤维蛋白原水平无关。基于这些观察，这一应用重点是纤维蛋白原活性和表达的潜在机制。其具体目的是：1)识别调节纤维蛋白原表达的顺式和反式作用的SNPs。这将使用来自Framingham心脏研究参与者的Share 55万个SNP集的数据来完成。2)确定SNP标记的单倍型区块内的候选基因。这将使用候选基因方法来识别可能调节肝脏表达的基因？纤维蛋白原水平。这些特定的目的将检验这样的假设，即除了基因(FGG)内的候选SNPs外，新的全基因组SNPs还调节？纤维蛋白原和纤维蛋白原与总纤维蛋白原的比值。总而言之，这些特定的目标将使我们能够从SNP标记的单倍型块中识别最可能的候选基因。我们的长期目标是超越目前的R21，最终利用这些信息开发siRNAs来抑制候选基因在肝细胞中的表达，以测试它们在链表达中的作用。与公共卫生相关：纤维蛋白原是凝血因子纤维蛋白原的同种形式，纤维蛋白原是一种新出现的心血管疾病危险因素。这项应用的长期目标是阐明纤维蛋白原的基因调控，为了解其在心血管疾病中的作用奠定基础。

DESCRIPTION (provided by applicant): This application's long-term goal is to elucidate the genetic regulation of the ' fibrinogen isoform as a foundation for understanding its role in cardiovascular disease. The specific hypothesis behind the proposed research is that elevated ?' fibrinogen levels lead to cardiovascular disease, based on several observations. First, purified ?' fibrinogen forms clots in vitro that are mechanically stiffer than unfractionated fibrinogen. Second, purified ' fibrinogen forms fibrin clots that are resistant to fibrinolysis. Third, decreased ?' fibrinogen levels are correlated with venous thrombosis and thrombotic microangiopathy. And fourth, elevated ?' fibrinogen levels are strongly associated with arterial cardiovascular disease, independent of total fibrinogen levels, as shown in the Stockholm Coronary Artery Disease Risk Factor study and the Framingham Heart Study. Based on these observations, this application focuses on the mechanisms underlying ' fibrinogen activity and expression. The specific aims are to: 1) Identify cis- and trans-acting SNPs that modulate ' fibrinogen expression. This will be accomplished using data from a SHARe 550K SNP set of Framingham Heart Study participants. 2) Identify candidate genes within the SNP-tagged haplotype block. This will be accomplished using the candidate gene approach to identify liver-expressed genes that are likely to regulate ?' fibrinogen levels. These specific aims will test the hypothesis that novel genome-wide SNPs, in addition to candidate SNPs within the gene (FGG), regulate the levels of ?' fibrinogen and the ratio of ' fibrinogen to total fibrinogen. Together, these specific aims will allow us to identify the most likely candidate genes from within the SNP- tagged haplotype block. Our long-term goal beyond the present R21 is to ultimately use this information to develop siRNAs to knock down expression of the candidate genes in liver cells in order to test their role in ' chain expression. PUBLIC HEALTH RELEVANCE: Fibrinogen is an isoform of the blood clotting factor fibrinogen that is a newly-emerging cardiovascular disease risk factor. This application's long-term goal is to elucidate the genetic regulation of ' fibrinogen as a foundation for understanding its role in cardiovascular disease.