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 凝血因子VIII（FVIII）及其载体蛋白血管性血友病因子（VWF）在血液中起重要作用 凝血我们已经领导了全基因组关联研究，成功地确定了基因座有助于血浆 FVIII和VWF水平。许多已确定的遗传决定因素影响FVIII和VWF，而一些基因座 仅影响FVIII或VWF。我们进行了孟德尔随机化（MR），发现 基因决定的FVIII和VWF水平与几种动脉和静脉血栓性疾病。尽管有这些 尽管有进展，但在理解FVIII和VWF水平的遗传学方面仍存在知识差距，特别是在 未被充分研究的人群，如西班牙裔。更复杂的调节机制，如上位性和 表观遗传学仍然没有特征。最后，由于许多已鉴定的基因座在FVIII和 由于VWF的存在，很难确定它们在多大程度上发挥独立或协调的作用， 血栓性疾病的病理学。 更新R 01 HL 139553的总体目标是产生关于遗传学的新生物学知识。 和表观遗传调控的FVIII和VWF在多血统人群中，并获得更好的了解如何 这些止血因子在血栓性疾病的发展中起作用。在目标1中，我们将确定新的 通过测量14，000名患者血浆中的FVIII和VWF， 来自西班牙裔社区健康研究/拉丁美洲人研究的西班牙裔全基因组序列数据， 将其与来自CHARGE和TOPMed的现有多祖先数据相结合。我们还将评估上位效应 ABO血型在目标2中，我们将进行表观基因组关联研究，以检查 FVIII和VWF水平与基因组中CpG位点血液甲基化水平的相关性， 与这些CpG位点相关的遗传变异。我们将描述已知和新发现的功能 使用体外和体内模型，从目的1和2的基因座。在目标3中，我们将使用遗传变异调节 在目的1和2中确定FVIII和VWF作为MR分析中的遗传工具，以评估FVIII和/或VWF是否 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， 凝结的相对重要性（即，通过FVIII）或血小板（即，通过VWF）在不同的血栓性疾病中， 从而告知现有和新疗法的靶向使用。