Genetic Modifiers of von Willebrand Disease

描述（由申请人提供）：血管性血友病（VWD）是一种常见且高度可变的出血性疾病，具有不完全外显性和可变表达性。ABO血型是唯一具有良好特征的人类血管性血友病因子（VWF）遗传修饰因子，其贡献高达30%的遗传成分。即使在同一家族中，VWD患者的出血倾向也有相当大的差异，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。本提案的总体目标是确定人类VWF水平和出血严重程度的修饰基因位点。通过连锁作图，使用大谱系，我们的目标是发现对VWF水平和出血严重程度起修饰作用的基因。本研究将使用通过多机构努力收集的扩展谱系和小型核心家庭进行。目标1将侧重于收集大型VWD家系的样本及其表型表征。我们已经收集并鉴定了来自印第安纳州北部的758名成员Amish谱系和来自爱荷华州的24名成员谱系诊断为VWD。我们已经确定并将通过合作努力招募8个额外的谱系，每个谱系至少有6个受影响的个体。目的2将确定VWF水平和这些大型VWD家系出血的候选遗传区域。我们将对阿米什人和爱荷华人的血统进行全基因组扫描。我们还将对所有其他谱系进行基因组扫描。目标3将侧重于在全基因组扫描中鉴定的位点的精细定位和随后的基因/突变鉴定。我们将通过与罗伯特·蒙哥马利博士合作，对来自爱荷华州和加拿大、欧洲和美国其他地区的非亲属家庭进行连锁不平衡检验，缩小候选地区的范围。将检查这些区域的候选基因，这些候选基因在生物学上似乎是合理的，可以作为VWD的修饰因子。候选基因将被测序，鉴定出的突变将通过进一步的测序和共分离分析来确认。总的来说，我们相信该项目将为VWD的遗传学提供新的见解，并可能对了解出血和血栓形成的遗传基础具有重要意义。

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.