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

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。尽管疾病负担很大，但没有药物治疗可以减缓其 这在很大程度上是由于我们对这种疾病的了解不够。随着预期的增长， 由于美国人口老龄化造成的AS负担，旨在了解风险因素的研究， AS的病因是必要的，并可能导致新的治疗策略。我们最近在新英格兰报道了 医学杂志，LPA的遗传变异与主动脉瓣钙（AVC）和 临床AS涉及循环脂蛋白（a），一种常见的胆固醇形式，是主动脉瓣狭窄的原因。 虽然Lp（a）的作用还不完全清楚，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（LpPLA 2）。OxPL（和它们被氧化裂解的副产物） LpPLA 2）是促动脉粥样硬化、促炎症和促钙化的，这表明oxPL和Lp-PLA 2可能是 Lp（a）介导的AS的主要决定因素。我们提出了描述Lp（a），oxPL和 LpPLA 2及其与横截面上AVC患病率和纵向进展的潜在相互作用， 使用分子和遗传流行病学方法，在FOS研究（FOS）和多 动脉粥样硬化的种族研究（梅萨）。通过合并两个正在进行的大型NHLBI队列，我们将创建一个 全世界最大的序贯瓣膜成像队列（n= 7，178;包括序贯AVC 在6，777名参与者中进行测量），以实现以下目标：具体目标1。涉及循环 Lp（a）、oxPL和LpPLA 2水平与FOS和梅萨中AVC的存在和进展的关系 参与者，并使用正式调解和/或 不一致性分析我们将包括1,298名FOS参与者和5,880名梅萨参与者， AVC数据，并将生物标志物水平与横截面AVC患病率和AVC进展相关 纵向使用调整已知混杂因素的多变量分析。具体目标2。评价 用于通过LDL-C和/或炎症易感性对Lp（a）（和/或oxPL）进行有效修饰 FHS和梅萨参与者中AVC的存在和进展的关系。我们将 开发多变量模型，纳入适当的相互作用项，以评估AVC患病率交叉 节段性和纵向AVC进展。具体目标3。提供证据以支持 使用孟德尔遗传算法分析这些生物标志物与AVC存在/进展之间的因果关系 FHS和梅萨参与者的随机化。我们建议的项目与 2011年国家心肺和血液研究所AS工作组的建议，并建议 直接解决几个重要的研究优先事项。从我们提出的项目的结果将导致新的 这将有助于深入了解AVC的发病机制，并可能为预防和治疗AS提供新的方法。

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.