Using genomics and functional biology to understand fibrinogen and its effect on thrombotic and atherosclerotic outcomes

项目总结 纤维蛋白原是正常凝血所必需的，也是炎症的重要组成部分。 小路。这两个过程在血栓形成和动脉粥样硬化的发展过程中紧密交织在一起。 疾病。我们可以从功能上更好地了解纤维蛋白原的生物学和病理生理作用 表征基因组对循环纤维蛋白原水平的贡献。在心脏和老龄化队列中 在基因组流行病学(CHARE)联盟的研究中，我们开展了全基因组关联研究 寻找纤维蛋白原水平的遗传决定因素。这些研究涉及数以万计的 纤维蛋白原结构基因内的个体和已识别的变异，以及42个其他显著相关的 精神错乱。然而，关联研究并没有解释这些基因座上的哪些基因在功能上影响纤维蛋白原。 级别。确定这些基因是否通过炎症途径起作用也很重要。这个 该项目的目标是利用我们在基因组研究和功能生物学方面的专业知识来产生新的 关于纤维蛋白原基因组调控的生物学知识和表征两者之间的关系 纤维蛋白原与血栓和动脉粥样硬化性疾病。 我们的研究设计使具有凝血专业知识的功能生物学家之间能够交换信息 生物化学和血栓病理生理学，以及来自Charge联盟的遗传流行病学家。这个 跨学科团队将实现三个具体目标。首先，我们将使用siRNA基因沉默来询问 GWA42个座位上与纤维蛋白原水平相关的基因决定了它们对纤维蛋白原的影响 转录、翻译和分泌，并确定这些基因是否通过 炎症(IL6-STAT3)途径。第二，我们将进行表观基因组范围的关联研究 全基因组CpG位点的纤维蛋白原水平和血液甲基化水平之间的关联。这些 结果与遗传数据相结合，以识别与CpG位点(MeQTL)相关的遗传变异 也与纤维蛋白原水平有关。纤维蛋白原相关meQTL上的候选基因也将 使用建议的功能生物学方法进行评估。第三，我们将评估因果关系 用孟德尔随机化方法研究纤维蛋白原与血栓和动脉粥样硬化性疾病之间的关系。 从功能生物学实验中获得的知识将用于改进遗传仪器 纤维蛋白原，并另外创造了一种仅由与IL6-STAT3相关的变体组成的仪器 路径。 这种团队科学方法在其实验设计和揭示重要的、 影响人类健康的新信息通过将基因组关联研究结果转化为明确的 了解纤维蛋白原在血栓和动脉粥样硬化性疾病中的作用。

PROJECT SUMMARY Fibrinogen is essential for normal blood coagulation and is an integral component of inflammatory pathways. These two processes are deeply intertwined in the development of thrombotic and atherosclerotic diseases. We can better understand the biological and pathophysiological actions of fibrinogen by functionally characterizing the genomic contribution to circulating fibrinogen levels. In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, we carried out genome-wide association studies (GWAS) in search of genetic determinants of fibrinogen levels. These studies involved tens of thousands of individuals and identified variants within fibrinogen structural genes, as well as 42 other significantly associated loci. However, association studies do not explain which genes at these loci functionally influence fibrinogen levels. It is also important to determine whether genes at these loci act through inflammatory pathways. The goal of this project is to leverage our expertise in genomic studies and functional biology to generate new biological knowledge about the genomic regulation of fibrinogen and to characterize the relationship between fibrinogen and thrombotic and atherosclerotic disease. Our study design enables information exchange between functional biologists with expertise in coagulation biochemistry and thrombosis pathophysiology, and genetic epidemiologists from the CHARGE consortium. The interdisciplinary team will carry out three specific aims. First, we will use siRNA gene silencing to interrogate genes at 42 loci identified by GWAS to be associated with fibrinogen levels, determine their effect on fibrinogen transcription, translation, and secretion, and establish whether these genes modulate fibrinogen levels via an inflammatory (IL6-STAT3) pathway. Second, we will perform an epigenome-wide association study to examine the association between fibrinogen levels and blood methylation levels at CpG sites across the genome. These results are integrated with genetic data to identify genetic variants associated with CpG sites (meQTLs) that are also associated with fibrinogen levels. Candidate genes at fibrinogen-associated meQTLs will also be evaluated using the proposed functional biological methods. Third, we will assess the causal relationship between fibrinogen and thrombotic and atherosclerotic disease using a Mendelian Randomization approach. Knowledge gained from the functional biology experiments will be used to refine the genetic instrument for fibrinogen and additionally create an instrument that is composed only of variants related to the IL6-STAT3 pathway. This team science approach is innovative in its experimental design and in its potential to reveal important, new information impacting human health by translating results of genomic association studies into a clear understanding of fibrinogen's role in thrombotic and atherosclerotic disease.