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

目前动脉粥样硬化性心血管疾病(ASCVD)一级和二级预防指南， 包括冠心病(CHD)、外周动脉疾病(PAD)和脑血管疾病 统一应用风险因素修改，而不考虑心血管疾病亚型，尽管有越来越多的证据表明 这些疾病中的每一种都有特定的潜在病理生物学。大规模的基因研究发现了新的 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 CHD和PAD。这项工作证明了危险因素和治疗方法对血管领域的特定影响， 预防和治疗动脉粥样硬化性心血管疾病的激励疾病的具体方法。 不幸的是，脑血管疾病的基因研究一直滞后。现有的研究倾向于集中在 早期亚临床动脉粥样硬化(颈动脉内膜/中层厚度[cIMT])或晚期结局 (缺血性中风)。对实际的动脉粥样硬化性脑血管疾病的研究，以颈动脉狭窄的形式存在 受到样本量较小的限制。 退伍军人百万计划(MVP)于2011年启动，旨在研究基因、生活方式和军事接触 影响健康和疾病，为推进动脉粥样硬化的遗传学提供了独特的机会 通过对脑血管疾病颈动脉狭窄的研究。为了做到这一点，我们开发了一种经过验证的自然 语言处理(NLP)算法用于从成像中提取颈动脉狭窄程度的定量测量 退伍军人管理局电子健康记录(EHR)中的报告，促进疾病易感性和 进步。这一建议的首要假设是颈动脉斑块的发展、进展 狭窄和由此导致的缺血性中风代表着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。为了解决这一假设，我们将进行全基因组关联 疾病易感性和疾病进展的研究。这些分析的结果将被用于 遗传因果推断实验：1.量化传统危险因素对高危人群的因果影响 颈动脉狭窄的易感性；2.确定颈动脉狭窄进展的原因危险因素；以及 3.利用基因组结构确定颈动脉狭窄和缺血性卒中的共同遗传结构 方程建模。 该项目的成功完成将阐明传统危险因素在颈动脉狭窄中的作用，确定 预防和治疗的新机遇，并为量身定做的精准医学奠定基础 退伍军人颈动脉狭窄的治疗和卒中预防方法。

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.