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

基本信息

批准号：
9805684
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
项目类别：
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/9805684
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&apos 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

项目摘要

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）是由第二性染色体完全或部分丢失引起的最常见的性染色体非整倍体。患有 TS 的人在表型上是女性，因为他们保留 X 染色体的一份完整副本。这种情况会导致对以下疾病的敏感性大大增加具有明显性别偏见的常见疾病。事实上，TS 中不良的健康轨迹导致了早期心血管相关疾病造成的死亡是前所未有的。特别是，患有 TS 的个体约为 100 倍比整倍体女性更有可能出生时患有二尖瓣主动脉瓣 (BAV)。 BAV 是最常见的人类发生先天性心脏病，最常见于整倍体人群中的男性。拥有 a BAV 使受影响的个体易患成人瓣膜疾病，包括钙化、瓣膜增厚和狭窄。主动脉瓣关闭不全可能会增加感染性心内膜炎的风险。胸主动脉近 50% 的 BAV 患者会出现动脉瘤，这可能导致主动脉夹层和死亡。这先天性心脏病 BAV 与晚发性主动脉疾病（称为二尖瓣疾病）之间的关系主动脉瓣疾病或 BAVD）尚不清楚。有证据表明改变血流动力学起着动脉瘤进展中的作用，但很明显，患有 BAVD 的个体具有动脉瘤易感主动脉原因不明。尽管这种疾病很严重，但人们对这种疾病的认识却进展甚微。病因学。对导致 BAVD 的遗传变异的搜索结果较低，表明存在遗传异质性或其他机制在起作用。一种可能性是，差异参与主动脉瓣形成、主动脉壁发育和稳态的基因的表观遗传调控可能是危险因素。众所周知，TS 和整倍体之间的表观遗传景观存在显着差异个体，并且 TS 中存在差异基因表达。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控的个体差异 BAVD 风险。我们的初步数据显示NOTCH1通路中基因的甲基化存在差异患有 BAVD 的 TS 个体（病例）和没有 BAVD 的个体（对照）。这很重要，因为突变已知 NOTCH1 会导致非综合征型家族性 BAVD。在本研究中，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，以证实这一发现（目的 1).在目标 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效用与 BAVD 相关基因的差异表观遗传调控系统。我们拥有访问 TS 的独特权限通过 BioLINCC 中的 NHLBI GenTAC 存储库来支持这项研究。这个项目直接响应 NHLBI 战略愿景，特别是目标 3 下的研究任务决定心血管疾病性别相关差异的表观遗传因素。本研究的数据，带有关注 BAVD 的候选基因，将深入了解表观遗传学在这种严重疾病中的作用。