Genetic Determinants of Quantitative Variants of von Willebrand Disease

项目总结（见说明）： 1型和3型血管性血友病（VWD）分别代表了人类最常见的遗传性出血性疾病中最常见和最罕见的形式。这两种情况都是数量性状，1型VWD中血管性血友病因子（VWF）降低为轻度/中度，3型疾病为重度。在这项研究中，我们将进一步探讨这些疾病的发病机制。在该项目的目标#1中，我们将进行研究以进一步检查VWF基因中及其周围的序列变异在1型和3型VWD发病机制中的作用。这些研究将确定调控区变异、内含子变异和拷贝数变异的潜在致病作用。该项目的目标#2将涉及重新评估最近发表的CHARGE全基因组关联研究荟萃分析中的关联数据。这些研究将主要用于精细绘制CHARGE荟萃分析中描述的原始SNP关联。目标3和4将涉及研究，以解决CHARGE GWAS报告中报告的五种新的致病候选者的发现。在目标#3中，我们将进行研究以评估CHARGE中鉴定的两种候选物的作用，这两种候选物似乎有可能在VWF生物合成、储存和/或分泌中发挥作用。这些研究将涉及细胞生物学和遗传学方法的组合，以确定Syntaxin结合蛋白5（STXBP 5）和Syntaxin 2（STX 2）在调节VWF合成和从细胞释放中的作用。与评估正常STXBP 5和STX 2功能的研究平行，我们将在我们的1型和3型VWD人群中寻找这些蛋白的变体，并将确定我们已经建立的实验系统中所选变体的影响。最后，在目标#4中，我们将使用生物学和遗传学的类似组合来研究受体C型凝集素结构域家族4成员M、稳定蛋白-2和A类清道夫受体成员5加速清除VWF的影响。在描述了 正常受体在结合和清除VWF中的作用，我们将评估从我们的1型VWD患者队列的遗传搜索中获得的受体的变体形式的影响。

PROJECT SUMMARY (See instructions): Type 1 and 3 von Willebrand disease (VWD) represent the most frequent and rarest forms, respectively of the most common inherited bleeding disorder described in humans. Both conditions are quantitative traits with reductions of von Willebrand factor (VWF) being mild/moderate in type 1 VWD and severe in type 3 disease. In this research proposal, we will further pursue the pathogenesis of these conditions. In Aim #1 of the project we will carry out studies to further examine the role of sequence variation in and around the VWF gene in the pathogenesis of type 1 and 3 VWD. These studies will determine the potential pathogenetic role of regulatory region variants, intronic variants and copy number variation. Aim #2 of the project will involve a re-assessment of the association data presented in the recently published CHARGE genome-wide association study meta-analysis. These studies will be performed primarily to fine-map the original SNP associations described in the CHARGE meta-analysis. Aims 3 and 4 will involve studies to address the finding of five novel pathogenetic candidates reported in the CHARGE GWAS report. In Aim #3 we will perform studies to evaluate the role of two candidates identified in CHARGE that appear to have the potential to play a role in VWF biosynthesis, storage and/or secretion. These studies will involve a combination of cell biology and genetic approaches to determining the role of Syntaxin Binding Protein 5 (STXBP5) and Syntaxin 2 (STX2) in regulating VWF synthesis and release from cells. In parallel with the studies to evaluate normal STXBP5 and STX2 function, we will search for variants of these proteins in our type 1 and 3 VWD populations and will determine the influence of selected variants in the experimental systems that we have established. Finally, in Aim #4 we will use a similar combination of biology and genetics to investigate the influence of accelerated clearance of VWF by the receptors C-type lectin domain family 4 member M, Stabilin-2 and Scavenger receptor class A member 5. Again, after characterizing the role of the normal receptors in binding to and clearing VWF, we will evaluate the influence of variant forms of the receptors derived from a genetic search of our type 1 VWD patient cohorts.