Analysis of Whole Genome Sequence and Hemostasis Phenotypes

全基因组序列和止血表型分析

• 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
• 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

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.

项目摘要 凝结因子VIII（FVIII）及其载体蛋白von Willebrand因子（VWF）在血液中起着至关重要的作用 凝血。我们领导了全基因组关联研究，该研究成功地鉴定了有助于等离子体的基因座 FVIII和VWF水平。许多确定的遗传决定因素都会影响FVIII和VWF，而某些基因座 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 遗传确定的FVIII和VWF水平有几种动脉和静脉血栓性疾病。尽管如此 进步，知识差距仍然在理解FVIII和VWF水平的遗传学方面，尤其是在 研究的人口，例如西班牙裔。更复杂的监管机制，例如上学和 表观遗传学仍然没有表征。最后，因为许多确定的基因座都在FVIII和 vwf，很难确定他们在扮演独立或协调角色的程度 血栓疾病的病理学。 R01 HL139553续签的总体目标是产生有关遗传的新生物学知识 以及对多项式人群中FVIII和VWF的表观遗传调节，并更好地了解 这些止血因素在血栓性疾病的发展中起作用。在AIM 1中，我们将确定新的 通过测量血浆中的FVIII和VWF从14,000来测量FVIII和VWF，并改善现有基因座的精细映射 来自西班牙裔社区健康研究 /拉丁裔和研究的整个基因组序列数据 将其与现有的多功能数据结合起来，并获得顶部。我们还将评估上任效应 与ABO血液组。在AIM 2中，我们将进行一项范围眼元组的关联研究，以检查 FVIII和VWF水平与基因组的CPG部位的血液甲基化水平的关联，并鉴定 与这些CpG位点相关的遗传变异。我们将表征已知和新确定的功能 AIMS 1和2的基因座使用体外和体内模型。在AIM 3中，我们将使用调节的遗传变异 在目标1和2中鉴定为MR分析中的FVIII和VWF作为遗传工具，以评估FVIII和/或 VWF水平与几种动脉和静脉血栓性疾病的风险有因果关系。预期 结果应鉴定并验证了FVIII和VWF的新型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。 预计这些结果将产生重要的积极影响，因为它们将提供证据 在不同的血栓性疾病中凝血（即通过FVIII）或血小板（即通过VWF）的相对重要性， 从而告知有针对性的现有疗法和新型疗法的使用。