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)分别是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，在1型VWD中von Willebrand因子(VWF)降低为轻度/中度，在3型VWD中为重度。在这项研究计划中，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，我们将开展研究，进一步研究VWF基因及其周围的序列变异在1型和3型VWD发病机制中的作用。这些研究将确定调节区变异、内含子变异和拷贝数变异的潜在致病作用。目的该项目的第二个项目将涉及对最近出版的CHARE全基因组关联研究荟萃分析中提出的关联数据进行重新评估。这些研究将主要是为了对电荷荟萃分析中描述的原始SNP关联进行精细定位。目标3和4将涉及研究，以解决在Charge Gwas报告中报告的五个新的致病候选对象的发现。在目标#3中，我们将进行研究，以评估两名被确定为负责人的候选人的作用，这两名候选人似乎有可能在VWF的生物合成、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相结合的方法，以确定合成素结合蛋白5(STXBP5)和合成素2(STX2)在调节细胞合成和释放VWF中的作用。在评估正常STXBP5和STX2功能的同时，我们将在1型和3型VWD人群中寻找这些蛋白质的变体，并确定选定的变体在我们建立的实验系统中的影响。最后，在目标#4中，我们将使用类似的生物学和遗传学组合来研究受体C型凝集素结构域家族4成员M、Stablin-2和Scavenger受体A类成员5加速清除VWF的影响。 对于正常受体在结合和清除VWF中的作用，我们将评估通过对我们的1型VWD患者队列进行遗传搜索而获得的不同形式受体的影响。

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.