Analysis of Whole Genome Sequence and Hemostasis Phenotypes

全基因组序列和止血表型分析

基本信息

批准号：
10654394
负责人：
PAUL STEFAN DE VRIES
金额：
$ 73.8万
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：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654394
关键词：
ABO blood group system Adhesions Affect Aging Biological Blood Blood Platelets Blood coagulation Carrier Proteins Catabolism Circulation Coagulation Process Complex Coronary Arteriosclerosis Data Development Endothelial Cells Epigenetic Process Ethnic Population Factor VIII Fibrin Gene Silencing Genes Genetic Genetic Determinism Genetic Epistasis Genome Genomics Goals Heart Hemostatic Agents Hemostatic function Hispanic Community Health Study/Study of Latinos Hispanic Populations Human In Vitro Ischemic Stroke Knowledge Liver Maps Measures Mediating Mendelian randomization Methylation Myocardial Infarction Outcome Pathology Peripheral arterial disease Phase Phenotype Plasma Play Population Protein Biosynthesis Research Resources Risk Role Sample Size Sampling Site Small Interfering RNA Testing Thrombosis Trans-Omics for Precision Medicine Umbilical vein Venous Work cohort epigenetic marker epigenetic regulation epigenome epigenome-wide association studies genetic variant genome wide association study genomic epidemiology genomic locus improved in vivo Model instrument mouse model multi-ethnic novel novel therapeutics prevent programs therapeutic target venous thromboembolism von Willebrand Factor whole genome

项目摘要

PROJECT SUMMARY Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) play an essential role in blood coagulation. We have led genome-wide association studies that successfully identified loci contributing to plasma FVIII and VWF levels. Many of the identified genetic determinants affect both FVIII and VWF, while some loci affect only FVIII or only VWF. We performed Mendelian randomization (MR) and found associations of genetically determined FVIII and VWF levels with several arterial and venous thrombotic diseases. Despite these advances, knowledge gaps remain in understanding the genetics of FVIII and VWF levels, especially in understudied populations such as Hispanics. More complex regulatory mechanisms such as epistasis and epigenetics remain uncharacterized. Finally, because many of the identified loci are shared between FVIII and VWF, it has been difficult to determine the extent to which they play an independent or coordinated role in the pathology of thrombotic disease. The overall goals of the renewal of R01 HL139553 are to generate new biological knowledge about the genetic and epigenetic regulation of FVIII and VWF in multi-ancestry populations and gain a better understanding of how these hemostatic factors play a role in the development of thrombotic diseases. In Aim 1, we will identify new genomic loci and improve fine-mapping of existing loci by measuring FVIII and VWF in plasma from 14,000 Hispanics with whole genome sequence data from the Hispanic Community Health Study / Study of Latinos and combining it with existing multi-ancestry data from CHARGE and TOPMed. We will also evaluate epistatic effects with the ABO blood group. In Aim 2, we will perform an epigenome-wide association study to examine the association of FVIII and VWF levels with blood methylation levels at CpG sites across the genome and identify genetic variants associated with these CpG sites. We will characterize the function of known and newly identified loci from Aims 1 and 2 using in vitro and in vivo models. In Aim 3, we will use the genetic variants regulating FVIII and VWF identified in Aims 1 and 2 as genetic instruments in MR analyses to assess whether FVIII and/or VWF levels are causally related to the risk of several arterial and venous thrombotic diseases. The expected outcomes are to have identified and validated novel genetic and epigenetic determinants of FVIII and VWF levels, and to have elucidated the independent or coordinated effects of FVIII and VWF in thrombotic diseases. These results are anticipated to have an important positive impact because they will provide evidence of the relative importance of coagulation (i.e., via FVIII) or platelets (i.e., via VWF) in different thrombotic diseases, thereby informing the targeted use of existing and novel therapies.

项目概要凝血因子 VIII (FVIII) 及其载体蛋白血管性血友病因子 (VWF) 在血液中发挥着重要作用凝固。我们领导了全基因组关联研究，成功识别了对血浆有贡献的基因座 FVIII 和 VWF 水平。许多已确定的遗传决定因素影响 FVIII 和 VWF，而一些位点仅影响 FVIII 或仅影响 VWF。我们进行了孟德尔随机化 (MR) 并发现了以下关联：基因决定的 FVIII 和 VWF 水平与多种动脉和静脉血栓性疾病有关。尽管有这些尽管取得了进展，但在了解 FVIII 和 VWF 水平的遗传学方面仍然存在知识差距，特别是在未被充分研究的人群，例如西班牙裔。更复杂的调节机制，例如上位性和表观遗传学仍未得到表征。最后，因为许多已确定的基因座在 FVIII 和 VWF，很难确定它们在多大程度上发挥独立或协调作用血栓性疾病的病理学。 R01 HL139553更新的总体目标是产生关于遗传的新生物学知识多祖先群体中 FVIII 和 VWF 的和表观遗传调控，并更好地了解如何这些止血因素在血栓性疾病的发展中发挥作用。在目标 1 中，我们将确定新的基因组位点，并通过测量 14,000 个血浆中的 FVIII 和 VWF 来改进现有位点的精细定位西班牙裔美国人的全基因组序列数据来自西班牙裔社区健康研究/拉丁裔和拉丁裔研究将其与 CHARGE 和 TOPMed 的现有多祖先数据相结合。我们还将评估上位效应与 ABO 血型。在目标 2 中，我们将进行一项表观基因组范围的关联研究来检验 FVIII 和 VWF 水平与整个基因组 CpG 位点的血液甲基化水平的关联，并确定与这些 CpG 位点相关的遗传变异。我们将描述已知和新识别的功能使用体外和体内模型从目标 1 和 2 中确定基因座。在目标 3 中，我们将使用基因变异来调节目标 1 和 2 中确定的 FVIII 和 VWF 作为 MR 分析中的遗传工具，以评估 FVIII 和/或 VWF 水平与多种动脉和静脉血栓性疾病的风险存在因果关系。预期的结果是确定并验证了 FVIII 和 VWF 的新遗传和表观遗传决定因素水平，并阐明了 FVIII 和 VWF 在血栓性疾病中的独立或协调作用。这些结果预计将产生重要的积极影响，因为它们将提供证据凝血（即通过 FVIII）或血小板（即通过 VWF）在不同血栓性疾病中的相对重要性，从而告知现有疗法和新疗法的针对性使用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment.

中风治疗后止血因素和出血转化的多特征遗传学研究。

DOI：
发表时间：
2024-04
期刊：
影响因子：
0
作者：
Gallego;Temprano;Cárcel;Muiño, Elena;Cullell, Natalia;Lledós, Miquel;Llucià;Martin;Sobrino, Tomás;Castillo, José;Millán, Mònica;Muñoz;López
通讯作者：
López

Investigation of the association of novel genetic factors on von Willebrand factor (VWF) plasma levels

新型遗传因素与血管性血友病因子 (VWF) 血浆水平关联的研究