Molecular and Genetic Epidemiology of Lp(a)-mediated Calcific Aortic Valve Disease

Lp(a) 介导的钙化性主动脉瓣疾病的分子和遗传流行病学

• 批准号: 9238536
• 负责人: George Thanassoulis
• 金额: $ 41.75万
• 依托单位: MCGILL UNIVERSITY HEALTH CTR RES INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238536
• 关键词: Address; Affect; Aging; Aortic Valve Stenosis; Atherosclerosis; Biological; Biological Markers; Blood; Blood Vessels; Calcified; Calcium; Cholesterol; Clinical; Cohort Studies; Complex; Data; Deposition; Development; Disease; Epidemiologic Methods; Etiology; Framingham Heart Study; Genetic; Genetic Predisposition to Disease; Image; Individual; Inflammation; Inflammatory; Journals; LDL Cholesterol Lipoproteins; Lead; Link; Lipoprotein (a); Measurement; Measures; Mediating; Mediation; Medical; Medicine; Modeling; Modernization; Modification; Molecular Epidemiology; Monoclonal Antibodies; Multi-Ethnic Study of Atherosclerosis; National Heart, Lung, and Blood Institute; New England; Oxides; Participant; Pathogenesis; Phospholipids; Physiological; Plasma; Population Research; Positioning Attribute; Predisposition; Prevalence; Prevention approach; Proteins; Randomized; Recommendation; Reporting; Research Design; Research Priority; Risk Factors; Role; Statistical Data Interpretation; Targeted Research; Testing; Western World; aortic valve; aortic valve disorder; burden of illness; calcification; cardiovascular imaging; cohort; fundamental research; genetic analysis; genetic epidemiology; genetic variant; insight; lipoprotein-associated phospholipase A(2); novel; novel strategies; offspring; treatment strategy; working group

Aortic stenosis (AS) is the most common form of valve disease in the western world and affects over 2.5 million individuals in the US. Despite the large burden of disease, there are no medical treatments to slow its development, due in large part to our incomplete understanding of this disease. With the expected increase in the burden of AS due to the aging US population, research targeted to understanding the risk factors and causes of AS is needed, and could lead to new treatment strategies. We recently reported in the New England Journal of Medicine, that genetic variants in LPA are strongly associated with aortic valve calcium (AVC) and clinical AS implicating circulating lipoprotein(a), an usual form of cholesterol as a cause of aortic stenosis. Although the role of Lp(a) is not fully understood, Lp(a) is a major carrier of circulating oxidized phospholipids (oxPL) and lipoprotein-associated phospholipase A2 (LpPLA2). OxPLs (and by-products of their cleavage by LpPLA2) are pro-atherogenic, pro-inflammatory and pro-calcifying, suggesting that oxPL and Lp-PLA2 may be major determinants of Lp(a)-mediated AS. We propose to characterize the relations of Lp(a), oxPL and LpPLA2 and their potential interactions with AVC prevalence cross-sectionally and progression longitudinally, using molecular and genetic epidemiology methods in the Framingham Offspring Study (FOS) and the Multi- Ethnic Study of Atherosclerosis (MESA). By combining two large ongoing NHLBI cohorts, we will create one of the largest cohorts worldwide with sequential valve imaging (n= 7,178; including sequential AVC measurements in 6,777 participants) to address the following aims: Specific Aim 1. To relate circulating levels of Lp(a), oxPL and LpPLA2 to the presence and progression of AVC in FOS and MESA participants and determine their relative contributions to AVC using formal mediation and/or discordance analysis. We will include 1,298 FOS participants and 5,880 MESA participants with available AVC data and relate the biomarker levels to AVC prevalence cross-sectionally and to AVC progression longitudinally using multivariable analyses adjusting for known confounders. Specific Aim 2. To evaluate for effect modification of Lp(a) (and/or oxPL) by LDL-C and/or predisposition to inflammation in the relations with presence and progression of AVC in FHS and MESA participants. We will develop multivariable models incorporating appropriate interaction terms to evaluate AVC prevalence cross- sectionally and AVC progression longitudinally. Specific Aim 3. To provide evidence in support of a causal association between these biomarkers and AVC presence/progression using Mendelian randomization in FHS and MESA participants. Our proposed project is well-aligned with the recommendations of the 2011 National Heart Lung and Blood Institute's AS Working Group and proposes to directly address several important research priorities. Findings from our proposed project will lead to new insights into the pathogenesis of AVC and may inform novel approaches for the prevention and treatment of AS.

主动脉瓣狭窄 (AS) 是西方世界最常见的瓣膜疾病，影响超过 250 万人 在美国的个人。尽管疾病负担巨大，但没有药物可以减缓其速度 的发展，很大程度上是由于我们对这种疾病的不完全了解。随着预期的增加 由于美国人口老龄化造成的 AS 负担，研究旨在了解风险因素和 我们需要找出 AS 的病因，并可能导致新的治疗策略。我们最近在新英格兰报道 《医学杂志》指出，LPA 的遗传变异与主动脉瓣钙 (AVC) 密切相关， 临床 AS 涉及循环脂蛋白（a），这是一种常见的胆固醇形式，是主动脉瓣狭窄的原因。 尽管 Lp(a) 的作用尚不完全清楚，但 Lp(a) 是循环氧化磷脂的主要载体 (oxPL) 和脂蛋白相关磷脂酶 A2 (LpPLA2)。 OxPL（及其裂解的副产品） LpPLA2) 具有促动脉粥样硬化、促炎症和促钙化作用，表明 oxPL 和 Lp-PLA2 可能是 Lp(a) 介导的 AS 的主要决定因素。我们建议描述 Lp(a)、oxPL 和 LpPLA2 及其与 AVC 横断面患病率和纵向进展的潜在相互作用， 在弗雷明汉后代研究 (FOS) 和多重研究中使用分子和遗传流行病学方法 动脉粥样硬化的种族研究（MESA）。通过合并两个正在进行的大型 NHLBI 队列，我们​​将创建一个 全球最大的序贯瓣膜成像队列（n = 7,178；包括序贯 AVC 6,777 名参与者的测量），以实现以下目标： 具体目标 1. 将循环联系起来 Lp(a)、oxPL 和 LpPLA2 水平与 FOS 和 MESA 中 AVC 的存在和进展有关 参与者并通过正式调解确定他们对 AVC 的相对贡献和/或 不一致分析。我们将包括 1,298 名 FOS 参与者和 5,880 名 MESA 参与者 AVC 数据并将生物标志物水平与 AVC 横断面患病率和 AVC 进展相关联 纵向使用多变量分析调整已知的混杂因素。具体目标 2. 评估 用于 LDL-C 和/或炎症倾向对 Lp(a)（和/或 oxPL）的影响 与 FHS 和 MESA 参与者中 AVC 的存在和进展的关系。我们将 开发包含适当交互项的多变量模型来评估跨群体 AVC 患病率 剖面和 AVC 纵向进展。具体目标 3. 提供证据支持 使用孟德尔模型分析这些生物标志物与 AVC 存在/进展之间的因果关系 FHS 和 MESA 参与者的随机化。我们提出的项目与 2011 年国家心肺和血液研究所 AS 工作组的建议，并提议 直接解决几个重要的研究重点。我们提议的项目的调查结果将带来新的结果 深入了解 AVC 的发病机制，并可能为预防和治疗 AS 提供新的方法。