Genome-wide Association Study for Gamma' Fibrinogen Expression

描述（由申请人提供）：本申请的长期目标是阐明纤维蛋白原亚型的遗传调控，作为了解其在心血管疾病中的作用的基础。这项研究背后的具体假设是提高了吗？根据几项观察，纤维蛋白原水平会导致心血管疾病。首先，净化？纤维蛋白原在体外形成的凝块比未分离的纤维蛋白原在机械上更硬。其次，纯化的纤维蛋白原形成抗纤维蛋白溶解的纤维蛋白凝块。第三，减少了？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，升高？斯德哥尔摩冠状动脉疾病危险因素研究和弗雷明汉心脏研究显示，纤维蛋白原水平与动脉性心血管疾病密切相关，独立于总纤维蛋白原水平。基于这些观察，本应用侧重于纤维蛋白原活性和表达的机制。具体目的是：1)鉴定调节纤维蛋白原表达的顺式和反式snp。这将使用来自Framingham心脏研究参与者的SHARe 550K SNP集的数据来完成。2)在snp标记的单倍型块中鉴定候选基因。这将通过候选基因方法来鉴定肝脏表达的基因，这些基因可能调节？纤维蛋白原水平。这些特定的目标将验证一个假设，即新的全基因组snp，以及基因内的候选snp (FGG)，调节？纤维蛋白原和纤维蛋白原与总纤维蛋白原的比值。总之，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。除了目前的R21，我们的长期目标是最终利用这些信息开发sirna来降低肝细胞中候选基因的表达，以测试它们在“链表达”中的作用。公共卫生相关性：纤维蛋白原是凝血因子纤维蛋白原的一种异构体，是一种新出现的心血管疾病危险因子。该应用程序的长期目标是阐明纤维蛋白原的遗传调控，作为了解其在心血管疾病中的作用的基础。

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.