Genetic Etiology of Bicuspid Aortic Valve Disease

描述(由申请人提供)： 二尖瓣主动脉瓣(BAV)是最常见的先天性心脏畸形，发病率为0.5-1.2%。超过50%的BAV患者在一生中出现早期钙化性主动脉瓣狭窄或关闭不全，占美国每年进行的30,000例主动脉瓣置换手术(AVR)的40%左右。然而，我们对BAV到主动脉瓣狭窄和关闭不全以及胸主动脉瘤/夹层的病因、细胞生物学和疾病进展的修饰物知之甚少。因此，拟议研究的一个关键目标是阐明BAV病理中涉及的遗传途径。有非常有力的证据证明BAV的遗传性，估计高达89%。在少数家族中，NOTCH1的高穿透性显性突变与BAV有关。还发现了其他易感基因座，但没有复制。然而，大多数BAV患者没有报告家庭成员患有BAV，约94%的人没有NOTCH1突变。因此，我们的目标是通过利用多个BAV患者队列来确定BAV的遗传原因(S)，这些患者已经和没有经历过动静脉曲张。通过全外显子组测序和随后的基因分型来确定BAV相关突变的目的是确定BAV的病因，重要的是确定BAV的临床后果所基于的遗传背景，从而集中研究降低成年后钙化性主动脉瓣疾病的风险的途径。我们将通过研究牛细小病毒的胚胎学分子生物学，使用斑马鱼Morolino模型来模拟已发现的人类突变(S)，来支持和扩大测序和基因分型工作的结果。我们将尝试用三种方法识别影响BAV钙化主动脉瓣病变进展的遗传和非遗传因素。首先，我们将使用已经和还没有接受过主动脉钙化性狭窄的房室成形术的BAV队列来确定临床和遗传因素。 主动脉瓣钙化的进展。我们将在已经开发的老化小鼠GATA5基因敲除模型中研究这些因素。GATA5基因敲除小鼠具有25%的BAV外显率，因此可以在共同的遗传背景上研究改变BAV钙化的因素。我们还将收集来自二尖瓣和三尖瓣的钙化主动脉瓣组织，以确定这些不同血流动力学和遗传背景之间的表达差异。我们的主要目的是确定二尖瓣主动脉瓣疾病及其随后的钙化性主动脉狭窄的遗传原因。我们认为，RFA和这项建议提供了一种可信和最佳的机制来解决BAV治疗钙化性主动脉狭窄的问题。我们相信，这些方法将在BAV研究和潜在的患者管理方面取得关键进展。 (摘要结束)

DESCRIPTION (provided by applicant): Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation, occurring in 0.5-1.2% of the US population. Over 50% of patients with BAV develop early calcific aortic valve stenosis or incompetence in their lifetime and accounts for ~40% of the >30,000 aortic valve replacements (AVRs) performed in the US each year. Yet, we know little of the etiology, cellular biology and modifiers of disease progression for BAV to aortic valve stenosis and incompetence, and thoracic aortic aneurysm/dissection. Therefore, a critical goal of the proposed studies is to elucidate the genetic pathways involved in BAV pathology. There is very strong evidence for heritability of BAV, with estimates as high as 89%. In a few families, highly-penetrant dominant mutations of NOTCH1 have been associated with BAV. Additional susceptibility loci have also been identified but not replicated. However, a majority of individual with BAV do not report family members with BAV and ~94% do not possess a NOTCH1 mutation. We therefore aim to identify the genetic cause(s) of BAV by utilizing multiple cohorts of individuals with BAV who have, and have not, undergone AVR. The purpose of identifying BAV-associated mutations by whole-exome sequencing and subsequent genotyping is to establish the cause of BAV and importantly, the genetic background on which the clinical consequences of BAV are based, thus focusing research on pathways to attenuate the risk of calcific aortic valve disease in adulthood. We will support and expand the findings of sequencing and genotyping efforts by investigating the embryologic molecular biology of BAV, using Zebrafish morpholino models to mimic the identified human mutation(s). We will to attempt to identify genetic and non-genetic factors that impact on the progression of BAV calcific aortic valve disease using three methods. First, we will use BAV cohorts who have, and have not yet, undergone AVR for calcific aortic stenosis, to identify clinical and genetic factors that determine progression of aortic valve calcification. We will investigate these factors in an already-developed aging mouse GATA5 knockout model. The GATA5 knockout mouse has a 25% BAV penetrance, thus allowing investigation of the factors that alter calcification of the BAV on a common genetic background. We will also use a collection of human calcified aortic valve tissue from bicuspid and tricuspid aortic valves to identify expression differences between these different hemodynamic and genetic backgrounds. Our over-arching purpose is identification of genetic causes of bicuspid aortic valve disease and its subsequent calcific aortic stenosis. We believe that the RFA and this proposal provide a credible and best mechanism for attacking the issue of calcific aortic stenosis with BAV. We believe these methods will allow for critical advances in BAV research and potentially, patient management. (End of Abstract)