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.

项目摘要纤维蛋白原对于正常血液凝结至关重要，是炎症的组成部分途径。这两个过程在血栓性和动脉粥样硬化的发展中深深交织在一起疾病。我们可以通过功能更好地了解纤维蛋白原的生物学和病理生理作用表征对循环纤维蛋白原水平的基因组贡献。在人群中的心脏和衰老基因组流行病学研究（电荷）联盟，我们进行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。这些研究涉及成千上万的个体并确定了纤维蛋白原结构基因内的变体，以及42个其他显着相关的基因座。但是，关联研究不能解释这些基因座的哪些基因在功能上影响纤维蛋白原水平。确定这些基因座的基因是否通过炎症途径起作用也很重要。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节的生物学知识，并表征纤维蛋白原和血栓性和动脉粥样硬化疾病。我们的研究设计实现了具有凝结专业知识的功能生物学家之间的信息交换来自电荷联盟的生物化学和血栓形成病理生理学以及遗传流行病学家。这跨学科团队将执行三个具体目标。首先，我们将使用siRNA基因沉默来审问 GWAS鉴定出与纤维蛋白原水平相关的42个基因座基因，确定其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的关联研究以检查整个基因组的CpG部位的纤维蛋白原水平与血液甲基化水平之间的关联。这些结果与遗传数据集成在一起，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。纤维蛋白原相关的MEQTL的候选基因也将是使用拟议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方法在纤维蛋白原和血栓性和动脉粥样硬化疾病之间。从功能生物学实验中获得的知识将用于完善基因仪器纤维蛋白原并创建一种仅由与IL6-Stat3相关的变体组成的仪器路径。这种团队科学方法的实验设计具有创新性，并且有可能揭示重要的，通过将基因组协会研究的结果转化为明确的新信息，从而影响人类健康了解纤维蛋白原在血栓性和动脉粥样硬化疾病中的作用。