Systems Genetics Approach to Intracranial Aneurysms

颅内动脉瘤的系统遗传学方法

基本信息

批准号：
10237316
负责人：
Rose Du
金额：
$ 73.61万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2019-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237316
关键词：
Accounting Address Adult Affect Algorithms Aneurysm Aneurysmal Subarachnoid Hemorrhages Animal Model Aortic Aneurysm Arteries Bayesian Modeling Bayesian Network Biological Biological Markers Blood Blood Cells Blood Tests Blood Vessels Blood specimen Brain Aneurysms Brain hemorrhage Cell Wall Cells Cephalic Collaborations Complex Data Development Disease Early Diagnosis Early identification Epigenetic Process Epilepsy Evaluation Future Gene Expression General Population Genes Genetic Genomics Genotype Goals Hemorrhage Heterogeneity Immune Individual Intracranial Aneurysm Investigation Lead Methods Methylation Multiomic Data Mutation Other Genetics Outcome Pathway interactions Patients Phenotype Population Process Prognosis Quantitative Trait Loci Research Risk Rupture Signal Pathway Source Stroke Subarachnoid Hemorrhage Surgeon Survivors System Techniques Tissue Sample Tissues Variant base bisulfite sequencing cell type cerebrovascular cohort cost effective data integration differential expression experience genetic approach genetic variant genome wide association study high risk high risk population insight learning network life time cost methylomics middle age mortality multiple data types novel novel therapeutic intervention peripheral blood predictive modeling screening transcriptome sequencing transcriptomics years of life lost

项目摘要

PROJECT SUMMARY Aneurysmal subarachnoid hemorrhage (SAH) is caused by ruptured intracranial aneurysms and affects a predominantly young population and results in a large number of productive life years lost with a high associated lifetime cost. Aneurysmal SAH carries a poor prognosis with greater than 50% mortality and only 25% of survivors with good outcome. Because a devastating hemorrhage is usually the initial presentation and because of the young population involved, cost-effective early detection of unruptured aneurysms that will lead to more focused screening is of paramount importance. The genetic basis of aneurysm formation has been confirmed by genome-wide association studies in which a number of associated genes have been identified. However, the genetic variants identified in these studies explain only a fraction of the phenotypic variance, suggesting the involvement of other genetic and epigenetic mechanisms. We hypothesize that both genetic and epigenetic changes are crucial components of aneurysm formation and aim to identify the key pathways involved using a systems genetics approach. Our research will provide mechanistic insights into the epigenetic/genetic targets in aneurysm formation which may lead to the development of novel therapeutic strategies and provide a cost-effective means to identify individuals at high risk of aneurysm formation.

项目概要动脉瘤性蛛网膜下腔出血（SAH）是由颅内动脉瘤破裂引起的，影响主要是年轻人口，导致大量生产性生命年损失相关的终生成本。动脉瘤性蛛网膜下腔出血预后不良，死亡率超过 50%，且仅 25%的幸存者预后良好。因为毁灭性的出血通常是最初的表现，由于涉及年轻人口，未破裂动脉瘤的早期发现具有成本效益，这将导致进行更有针对性的筛查至关重要。动脉瘤形成的遗传基础经全基因组关联研究证实，其中已鉴定出许多相关基因。然而，这些研究中发现的遗传变异只能解释表型变异的一小部分，表明其他遗传和表观遗传机制的参与。我们假设这两种遗传表观遗传变化是动脉瘤形成的关键组成部分，旨在确定关键途径涉及使用系统遗传学方法。我们的研究将为以下问题提供机制见解：动脉瘤形成中的表观遗传/遗传靶标可能会导致新治疗方法的开发策略并提供一种经济有效的方法来识别动脉瘤形成高风险的个体。