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，作为理解其在心血管疾病中作用的基础。拟议研究背后的具体假设是，升高？纤维蛋白原水平导致心血管疾病，基于几个观察。首先，净化？纤维蛋白原在体外形成比未分级的纤维蛋白原机械上更硬的凝块。第二，纯化的纤维蛋白原形成抵抗纤维蛋白溶解的纤维蛋白凝块。第三，减少？纤维蛋白原水平与静脉血栓形成和血栓性微血管病相关。第四，高？如斯德哥尔摩冠状动脉疾病危险因素研究和心脏病研究所示，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，本申请集中于纤维蛋白原活性和表达的潜在机制。具体目标是：1）鉴定调节纤维蛋白原表达的顺式和反式作用SNP。这将使用来自心脏研究参与者的SHARe 550K SNP集的数据来完成。2)在SNP标记的单倍型块内识别候选基因。这将是完成使用候选基因的方法，以确定肝脏表达的基因，有可能调节？纤维蛋白原水平这些具体的目标将测试的假设，新的全基因组的单核苷酸多态性，除了候选单核苷酸多态性内的基因（FGG），调节水平？纤维蛋白原和纤维蛋白原与总纤维蛋白原的比率。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出最可能的候选基因。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来敲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亚型，是一种新出现的心血管疾病风险因素。本申请的长期目标是阐明纤维蛋白原的遗传调控，作为理解其在心血管疾病中作用的基础。

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.