Genetic Modifiers of von Willebrand Disease

描述(申请人提供)：von Willebrand病(VWD)是一种常见的高度可变的出血性疾病，具有不完全的外显性和可变的表现性。ABO血型是唯一具有良好特征的人类Von Willebrand因子(VWF)遗传修饰者，其贡献高达30%的遗传成分。VWD患者的出血倾向表现出相当大的差异，即使在同一个家庭中也是如此，与VWF水平无关。因此，修饰基因极有可能影响表型。缺乏对VWD修饰基因的了解限制了诊断和治疗。这项建议的总体目标是确定影响人类VWF水平和出血严重程度的基因位点。通过连锁作图，利用大的家系，我们的目标是发现对VWF水平和出血严重程度起调节作用的基因。这项研究将使用通过多机构努力收集的扩展家系和小核心家庭进行。目标1将集中于从VWD大型家系中收集样本及其表型特征。我们已经收集并鉴定了来自印第安纳州北部的一个758人的阿米什家系和来自爱荷华州的一个被诊断为VWD的24人的家系。我们已经确定并将通过合作努力再招募至少6名受影响个人的8个家系。AIM 2将在这些VWD大型家系中确定VWF水平和出血的候选遗传区域。我们将对阿米什和爱荷华州的家系进行全基因组扫描。我们还将对所有其他家系进行基因组扫描。目标3将侧重于在全基因组扫描中确定的基因座的精细定位以及随后的基因/突变鉴定。我们将通过与Robert Montgomery博士的合作，在来自爱荷华州以及来自加拿大、欧洲和美国其他地区的家系中使用连锁不平衡测试来缩小候选区域。将对这些区域进行检查，以寻找从生物学角度看似乎可信的候选基因，作为VWD的修饰物。候选基因将被测序，已确定的突变将通过进一步的测序和共分离分析来确认。总体而言，我们相信这个项目将为VWD的遗传学提供新的见解，并可能对理解出血和血栓形成的遗传学基础具有重要意义。

DESCRIPTION (provided by applicant): Von Willebrand disease (VWD) is a common and highly variable bleeding disorder with incomplete penetrance and variable expressivity. The ABO blood group is the only well-characterized human genetic modifier of Von Willebrand Factor (VWF) with a contribution of up to 30% of the genetic component. Patients with VWD show considerable variation in bleeding tendency even within the same family, independently of VWF levels. Therefore it is highly likely that modifier genes influence the phenotype. Lack of understanding of VWD modifier genes limits diagnosis and treatment. The overall goal of this proposal is to identify genetic loci that are modifiers of VWF levels and bleeding severity in humans. Through linkage mapping, using large pedigrees, we aim to discover genes that exert a modifier effect on VWF levels and bleeding severity. This study will be performed using extended pedigrees and small nuclear families collected through a multi- institutional effort. Aim 1 will focus on the collection of samples from large pedigrees with VWD and their phenotypic characterization. We have already collected and characterized a 758-member Amish pedigree from northern Indiana and a 24-member pedigree from Iowa diagnosed with VWD. We have identified and will recruit 8 additional pedigrees of at least 6 affected individuals each through a collaborative effort. Aim 2 will identify candidate genetic regions for VWF levels and bleeding in these large pedigrees with VWD. We will perform a genome wide scan on the Amish and Iowa pedigrees. We will also conduct genome scans in all additional pedigrees. Aim 3 will focus on the fine mapping of loci identified in the genome-wide scans and subsequent gene/mutation identification. The candidate regions will be narrowed using linkage disequilibrium testing in the extended set of unrelated families from Iowa and in families from Canada, Europe and the rest of the US that are available to us through a collaboration with Dr. Robert Montgomery. The regions will be examined for candidate genes that seem plausible on biological grounds for serving as modifiers of VWD. Candidate genes will be sequenced, and identified mutations will be confirmed by further sequencing and co segregation analysis. Overall we believe that this project will provide new insights into the genetics of VWD and could have important implications for understanding the genetic basis of bleeding and thrombosis.