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

• 批准号: 10089477
• 负责人: Alanna C Morrison
• 金额: $ 77.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089477
• 关键词: Acute-Phase Reaction; Aging; Atherosclerosis; Biochemistry; Biological; Biology; Blood; Blood coagulation; Candidate Disease Gene; Coagulation Process; Coronary Arteriosclerosis; Data; Development; Epidemiologist; Epigenetic Process; Experimental Designs; Fibrinogen; Functional disorder; Gene Silencing; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genome; Genomics; Goals; Health; Heart; Human; IL6 gene; Individual; Inflammatory; Interleukin-6; Investigation; Knowledge; Malignant Epithelial Cell; Mendelian randomization; Methods; Methylation; Modeling; Myocardial Infarction; Outcome; Pathway interactions; Primary carcinoma of the liver cells; Process; Regulation; Research; Research Design; Research Personnel; Role; STAT3 gene; Science; Site; Small Interfering RNA; Stroke; Structural Genes; Testing; Thrombosis; Translating; Translations; Variant; Venous Thrombosis; carotid intima-media thickness; cohort; coronary artery calcification; epigenetic marker; epigenetic regulation; epigenome-wide association studies; experimental study; functional gain; genetic variant; genome wide association study; genomic epidemiology; genomic locus; innovation; instrument; interdisciplinary collaboration; thrombotic

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的血液凝固是必需的，并且是炎性细胞因子的组成部分。 途径。这两个过程在血栓形成和动脉粥样硬化的发展中深深交织在一起 疾病从功能上，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 在基因组流行病学（CHARGE）联盟的研究中，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。这些研究涉及数万名 个体和纤维蛋白原结构基因内鉴定的变体，以及42个其他显著相关的 的位点然而，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 程度.同样重要的是确定这些基因座上的基因是否通过炎症途径起作用。的 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， 关于纤维蛋白原的基因组调控的生物学知识，并表征 纤维蛋白原和血栓形成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进行信息交流 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。的 跨学科小组将实现三个具体目标。首先，我们将使用siRNA基因沉默来询问 通过GWAS鉴定的42个位点的基因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调节纤维蛋白原水平。 炎症（IL 6-STAT 3）通路。其次，我们将进行表观基因组关联研究， 纤维蛋白原水平与基因组中CpG位点的血液甲基化水平之间的关联。这些 将结果与遗传数据整合以鉴定与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处的候选基因也将被分析。 使用提出的功能生物学方法进行评价。第三，我们将评估因果关系 使用孟德尔随机化方法分析纤维蛋白原与血栓性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，并且另外创建仅由与IL 6-STAT 3相关的变体组成的仪器 通路 这种团队科学方法在其实验设计和揭示重要， 通过将基因组关联研究的结果转化为清晰的 了解纤维蛋白原在血栓性和动脉粥样硬化性疾病中的作用。