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

利用基因组学和功能生物学了解纤维蛋白原及其对血栓和动脉粥样硬化结果的影响

基本信息

批准号：
10552952
负责人：
Alanna C Morrison
金额：
$ 7.21万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

项目摘要

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.

项目概要纤维蛋白原对于正常凝血至关重要，并且是炎症的重要组成部分途径。这两个过程在血栓和动脉粥样硬化的发展过程中紧密交织在一起疾病。通过功能性研究，我们可以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。在心脏和衰老的队列中基因组流行病学研究（CHARGE）联盟，我们开展了全基因组关联研究（GWAS）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个体并确定了纤维蛋白原结构基因内的变异体，以及其他 42 个显着相关的基因基因座。然而，关联研究并没有解释这些位点上的哪些基因在功能上影响纤维蛋白原水平。确定这些位点的基因是否通过炎症途径发挥作用也很重要。这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以及表征之间的关系纤维蛋白原与血栓和动脉粥样硬化疾病。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形成病理生理学，以及来自 CHARGE 联盟的遗传流行病学家。这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 GWAS 确定的 42 个基因位点与纤维蛋白原水平相关，确定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。其次，我们将进行一项表观基因组范围的关联研究来检查纤维蛋白原水平与基因组 CpG 位点血液甲基化水平之间的关联。这些结果与遗传数据整合，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 的候选基因也将被使用所提出的功能生物学方法进行评估。第三，我们将评估因果关系使用孟德尔随机化方法来确定纤维蛋白原与血栓和动脉粥样硬化疾病之间的关系。从功能生物学实验中获得的知识将用于完善遗传仪器纤维蛋白原并另外创建了一种仅由与 IL6-STAT3 相关的变体组成的仪器途径。这种团队科学方法在实验设计和揭示重要的、通过将基因组关联研究的结果转化为明确的信息来影响人类健康了解纤维蛋白原在血栓和动脉粥样硬化疾病中的作用。