Epigenetic Contributions to Bicuspid Valve Aortopathy in Turner Syndrome

表观遗传对特纳综合征二尖瓣主动脉病变的影响

• 批准号: 9978913
• 负责人: CHERYL L MASLEN
• 金额: $ 11.55万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978913
• 关键词: Address; Adult; Affect; Aneuploidy; Aneurysm; Aorta; Aortic Aneurysm; Aortic Diseases; Aortic Valve Insufficiency; Biological Models; Blood; Blood specimen; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Cessation of life; Congenital Abnormality; Congenital Heart Defects; DNA; DNA Methylation; Data; Defect; Development; Disease; Disease susceptibility; Dissection; Epigenetic Process; Etiology; Female; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Heterogeneity; Genome; Genomic DNA; Goals; Health; Homeostasis; Human; Individual; Individual Differences; Infective endocarditis; Investigation; Investments; Life; Methylation; Mitral Valve; Modeling; Mus; Mutation; NOTCH1 gene; National Heart, Lung, and Blood Institute; Onset of illness; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Pattern; Phenotype; Pilot Projects; Play; Population; Predisposition; Registries; Risk; Risk Factors; Role; Sex Bias; Sex Chromosomes; Sex Differences; Smooth Muscle Myocytes; Stenosis; Study Subject; Testing; Thoracic Aortic Aneurysm; Time; Tissue-Specific Gene Expression; Tissues; Turner' s Syndrome; Vascular Smooth Muscle; Vision; Woman; X Chromosome; aortic valve; aortic valve disorder; bicuspid aortic valve; calcification; cardiovascular risk factor; cohort; disorder risk; epigenetic regulation; genetic variant; health difference; hemodynamics; high risk; induced pluripotent stem cell; insight; male; male Turner syndrome; men; methylation pattern; non-genetic; repository; sex chromosome aneuploidy

Turner syndrome (TS), which is caused by the complete or partial loss of the second sex chromosome, is the most commonly occurring sex chromosome aneuploidy. Individuals with TS are phenotypically female as they retain one complete copy of the X chromosome. This condition results in a greatly increased susceptibility for common diseases that have a significant sex bias. Indeed the poor health trajectory in TS resulting in early death from cardiovascular-related diseases is unprecedented. In particular, individuals with TS are ~100-times more likely than a euploid woman to be born with a bicuspid aortic valve (BAV). BAV is the most commonly occurring congenital heart defect in humans, and is most often seen in males in the euploid population. Having a BAV predisposes affected individuals to adult valve disease, including calcification, valve thickening and stenosis. Aortic regurgitation can occur promoting an increased risk for infective endocarditis. Thoracic aortic aneurysms occur in nearly 50% of people with BAV, which can result in aortic dissection and death. The relationship between having a congenital heart defect, BAV, and later onset aortic disease (known as bicuspid aortic valve disease or BAVD) is not well understood. There is evidence that altered hemodynamic flow plays a role in aneurysm progression, but it is clear that individuals with BAVD have an aneurysm susceptible aorta for unknown reasons. Despite the seriousness of this disease, few advances have been made in understanding the etiology. Searches for genetic variants that underlie the cause of BAVD have been of low yield indicating that there is genetic heterogeneity or that other mechanisms are in play. One possibility is that differences in epigenetic regulation of genes involved in aortic valve formation, and aortic wall development and homeostasis may be risk factors. It is known that the epigenetic landscape in TS differs significantly between TS and euploid individuals, and that there is differential gene expression in TS. In this pilot project we propose to explore individual differences in epigenetic regulation of gene expression using TS as a phenotypically extreme model of BAVD risk. Our preliminary data shows differential methylation of genes in the NOTCH1 pathway between TS individuals with BAVD (cases) and those with no BAVD (controls). This is significant as mutations in NOTCH1 are known to cause non-syndromic familial BAVD. In this study we will use DNA methyl-capture sequencing to identify differences in gene methylation patterns in a larger TS cohort to confirm this finding (aim 1). In aim 2 we will explore the utility of using iPS cell-derived vascular smooth muscle cell lines as a model system for differential epigenetic regulation of genes associated with BAVD. We have unique access to the TS cohort through the NHLBI GenTAC repository in BioLINCC to support this study. This project is directly responsive to the NHLBI Strategic Vision, particularly with regards to the mandate under objective 3 to study epigenetic factors that determine sex-related differences in cardiovascular disease. Data from this study, with a focus on candidate genes for BAVD, will provide insight into the role of epigenetics in this serious disease.

特纳综合征（TS）是由第二性染色体的完全或部分损失引起的，是 最常见的性爱染色体非整倍性。 TS的个体在表型上是女性 保留X染色体的一份完整副本。这种情况导致对 具有重大性偏见的常见疾病。实际上，TS的健康轨迹不佳，导致早期 与心血管有关的疾病死亡是前所未有的。特别是，TS的个体约为100次 比伯氏主动脉瓣膜（BAV）出生的多倍体女性更有可能。 BAV是最常见的 发生人类的先天性心脏缺陷，最常见于男性人群中的男性。有 BAV易于影响个体患有成人瓣膜疾病，包括钙化，瓣膜增厚和 狭窄。主动脉反流可以促进感染性心内膜炎的风险增加。胸部主动脉 动脉瘤发生在近50％的BAV患者中，这可能导致主动脉夹层和死亡。这 具有先天性心脏缺陷，BAV和后来发作主动脉疾病（称为双刺）之间的关系 主动脉瓣疾病或BAVD）尚不清楚。有证据表明，血流动力学的变化播放 在动脉瘤进展中的作用，但是很明显，Bavd患者具有动脉瘤易感主动脉的主动脉 未知原因。尽管这种疾病严重，但在理解方面几乎没有进步 病因。搜索BAVD原因的基础的遗传变异物的产量低，表明 存在遗传异质性或其他机制正在发挥作用。一种可能性是在 主动脉瓣形成涉及的基因的表观遗传调节以及主动脉壁发育和稳态 可能是风险因素。众所周知，TS中TS中的表观遗传景观在TS和Euploid之间显着不同 个体，并且Ts中存在差异基因的表达。在这个试点项目中，我们建议探索 使用TS作为表型极端模型的基因表达表观遗传调节的个体差异 Bavd风险。我们的初步数据显示了基因在Notch1途径中的差异甲基化 TS患有BAVD（案例）的人和没有BAVD的人（对照）。这很重要，因为突变 已知Notch1引起非综合性家族性Bavd。在这项研究中，我们将使用DNA甲基捕获 测序以确定较大TS队列中基因甲基化模式的差异以确认这一发现（AIM 1）。在AIM 2中，我们将探索使用IPS细胞衍生的血管平滑肌细胞系作为模型的实用性 与BAVD相关的基因差异表观遗传调节系统。我们有独特的访问TS 通过Biolincc的NHLBI GENTAC存储库来支持这项研究。这个项目直接 对NHLBI战略愿景的反应，特别是在目标3下的授权方面 确定心血管疾病中与性别相关的差异的表观遗传因素。这项研究的数据， 专注于BAVD的候选基因，将洞悉表观遗传学在这种严重疾病中的作用。