Leveraging the Genetics of carotid stenosis for identifying novel risk factors and therapeutic opportunities

利用颈动脉狭窄的遗传学来识别新的危险因素和治疗机会

• 批准号: 10589557
• 负责人: Scott Michael Damrauer
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589557
• 关键词: Address; Affect; Algorithms; Arteries; Atherosclerosis; Biological Markers; Biology; Blood Pressure; Blood Vessels; Brain; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Diseases; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Carotid Stenosis; Cerebrovascular Disorders; Coronary; Coronary artery; Coronary heart disease; Data; Data Scientist; Development; Diabetes Mellitus; Disease; Disease Progression; Disease susceptibility; Drug Targeting; Electronic Health Record; Epidemiologist; Equation; Gangrene; General Population; Genes; Genetic; Genetic Risk; Genetic study; Genomics; Genotype; Guidelines; Health; Heart; Hospitalization; Image; Intervention; Ischemic Stroke; Knowledge; Leg; Life Style; Link; Measures; Mediation; Mendelian randomization; Military Personnel; Modeling; Modification; Morbidity - disease rate; Myocardial Infarction; Natural Language Processing; Obesity; Outcome; Pain in lower limb; Pathway interactions; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Predisposition; Prevention; Prevention Guidelines; Prevention approach; Primary Prevention; Reporting; Risk; Risk Factors; Role; Sample Size; Secondary Prevention; Severities; Smoking; Stenosis; Stroke; Stroke prevention; System; Therapeutic; Therapeutic Intervention; Thick; Time; United States; Veterans; Work; blood lipid; cardiovascular disorder risk; clinically significant; disorder subtype; end stage disease; experimental study; genetic architecture; genome wide association study; genome-wide; health data; high risk; improved; individualized medicine; modifiable risk; mortality; new therapeutic target; novel; personalized approach; precision medicine; prevent; programs; risk prediction; risk variant; statistics; therapeutic target; trait

Current guidelines for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD), peripheral artery disease (PAD), and cerebrovascular disease, focus on the uniform application of risk factor modification irrespective of CVD subtype, despite rising evidence that each of these diseases has specific underlying pathobiology. Large scale genetic studies have identified new biology, clarified the role of modifiable risk factors, improved risk prediction, and identified therapeutic targets for CHD and PAD. This work has demonstrated vascular territory specific effects of risk factors and therapies, motivating disease specific approaches to prevention and treatment of atherosclerotic cardiovascular disease. Unfortunately, genetic studies of cerebrovascular disease have lagged. Extant studies have tended to focus on either early-stage subclinical atherosclerosis (carotid intima to media thickness [cIMT]) or late-stage outcomes (ischemic stroke). Studies of actual atherosclerotic cerebrovascular disease, in the form of carotid stenosis, have been limited by small sample size. The VA Million Veteran Program (MVP) was initiated in 2011 to study how genes, lifestyle, and military exposure affect health and disease and offers a unique opportunity to advance the genetics of atherosclerotic cerebrovascular disease through the study of carotid stenosis. To do this we have developed a validated natural language processing (NLP) algorithm to extract quantitative measures of carotid stenosis severity from imaging reports in the VA electronic health record (EHR), facilitating the study of both disease susceptibility and progression. The overarching hypothesis of this proposal is that the development of carotid plaque, progression of stenosis, and resulting ischemic stroke represent distinct pathobiological states, each offering a separate opportunity for therapeutic intervention. To address this hypothesis, we will conduct genome-wide association studies of both disease susceptibility and progression. The results from these analyses will be then used for genetic causal inference experiments to: 1. Quantify the causal impact of traditional risk factors on the susceptibility to carotid stenosis; 2. Determine the causal risk factors for the progression of carotid stenosis; and 3. Identify the shared genetic architecture of carotid stenosis and ischemic stroke using genomic structural equation modeling. Successfully completion of this project will clarify the role of traditional risk factors with carotid stenosis, identify novel opportunities for prevention and treatment, and establish the basis for tailored, precision medicine approaches to the treatment of carotid stenosis and stroke prevention for Veterans.

动脉粥样硬化性心血管疾病（ASCVD）一级和二级预防的现行指南， 包括冠心病（CHD）、外周动脉疾病（PAD）和脑血管疾病，重点 尽管越来越多的证据表明，无论 CVD 亚型如何，统一应用危险因素修正 这些疾病中的每一种都有特定的基础病理学。大规模遗传学研究发现了新的 生物学，阐明了可改变的危险因素的作用，改进了风险预测，并确定了治疗目标 冠心病和外周动脉疾病。这项工作证明了危险因素和治疗对血管区域的特定影响， 激发预防和治疗动脉粥样硬化性心血管疾病的特定疾病方法。 不幸的是，脑血管疾病的遗传学研究已经滞后。现有的研究往往集中于 早期亚临床动脉粥样硬化（颈动脉内膜至中层厚度 [cIMT]）或晚期结果 （缺血性中风）。对颈动脉狭窄形式的实际动脉粥样硬化性脑血管疾病的研究 受到样本量较小的限制。 退伍军人管理局百万退伍军人计划 (MVP) 于 2011 年启动，旨在研究基因、生活方式和军事暴露如何影响 影响健康和疾病，并为促进动脉粥样硬化的遗传学提供了独特的机会 通过研究颈动脉狭窄来研究脑血管疾病。为此，我们开发了一种经过验证的天然 语言处理 (NLP) 算法从成像中提取颈动脉狭窄严重程度的定量测量值 VA 电子健康记录 (EHR) 中的报告，促进疾病易感性和疾病的研究 进展。该提案的总体假设是颈动脉斑块的形成、进展 狭窄和由此产生的缺血性中风代表了不同的病理生物学状态，每种状态都提供了单独的 治疗干预的机会。为了解决这个假设，我们将进行全基因组关联 疾病易感性和进展的研究。这些分析的结果将用于 遗传因果推理实验旨在： 1. 量化传统风险因素对 颈动脉狭窄的易感性； 2.确定导致颈动脉狭窄进展的危险因素；和 3. 利用基因组结构识别颈动脉狭窄和缺血性中风的共同遗传结构 方程建模。 该项目的成功完成将阐明传统危险因素与颈动脉狭窄的作用，确定 预防和治疗的新机会，并为量身定制的精准医疗奠定基础 治疗退伍军人颈动脉狭窄和预防中风的方法。