Analysis of Whole Genome Sequence and Hemostasis Phenotypes

项目总结 凝血因子VIII(FVIII)及其载体蛋白von Willebrand因子(VWF)在血液中起重要作用 凝结。我们已经领导了全基因组关联研究，成功地确定了与血浆有关的基因座 FVIII和VWF水平。许多已识别的遗传决定因素同时影响FVIII和VWF，而一些基因座 仅影响FVIII或仅影响VWF。我们进行了孟德尔随机化(MR)，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。尽管如此 尽管取得了进展，但在理解FVIII和VWF水平的遗传学方面仍然存在知识差距，特别是在 西班牙裔等未被充分研究的人群。更复杂的监管机制，如上位性和 表观遗传学仍未确定其特征。最后，因为许多已识别的基因座在FVIII和FVIII之间是共享的 VWF，很难确定它们在多大程度上发挥着独立或协调的作用 血栓性疾病病理学。 更新R01 HL139553的总体目标是生成关于基因的新的生物学知识 以及FVIII和VWF在多个祖先群体中的表观遗传调节，并更好地了解如何 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人血浆中的FVIII和VWF来改进现有基因座的精细定位 具有拉美裔社区健康研究/拉美裔研究的全基因组序列数据的拉美裔美国人和 将其与Charge和TOPMed现有的多祖先数据相结合。我们还将评估上位效应 有ABO血型。在目标2中，我们将进行表观基因组范围的关联研究，以检查 FVIII和VWF水平与全基因组CpG位点血液甲基化水平的关系 与这些CpG位点相关的遗传变异。我们将描述已知的和新确定的功能 利用体外和体内模型研究AIMS 1和AIMS 2中的基因座。在目标3中，我们将使用基因变异来调节 FVIII和VWF在目标1和2中确定为MR分析中的遗传工具，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存在因果关系。预期中的 结果是确定和验证FVIII和VWF的新的遗传和表观遗传决定因素 并阐明FVIII和VWF在血栓性疾病中的独立或协同作用。 这些结果预计将产生重要的积极影响，因为它们将为 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， 从而告知对现有和新疗法的靶向使用。

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.