Molecular Epidemiology of Aortic Diameter and Subclinical Cardiovascular Disease

主动脉直径与亚临床心血管疾病的分子流行病学

基本信息

批准号：
9789359
负责人：
Allison L Kuipers
金额：
$ 9.12万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-23 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789359
关键词：
Address African Age Aneurysm Ankle Aorta Archives Area Arteries Atherosclerosis Award Biological Biological Assay Biological Markers Blood Pressure Blood Vessels Body Composition Brain natriuretic peptide Caliber Cardiac Cardiovascular Diseases Cardiovascular system Cause of Death Clinical Complex Coronary Data Diabetes Mellitus Disease Disease Marker Disease Progression Epidemiology European Event FZD1 gene Foundations Funding Gene Expression Generations Grant Health Human Hypertension Image In Vitro Individual Lead Length Link Location Longitudinal cohort study Malignant neoplasm of prostate Manuscripts Measurable Measurement Measures Mentored Research Scientist Development Award Microfluidics Molecular Molecular Disease Molecular Epidemiology Molecular Genetics N-terminal Nature Pathway interactions Physiologic pulse Plasminogen Activator Inhibitor 1 Play Population Group Population Heterogeneity Process Properdin Proprotein Convertases Protocols documentation Public Health Publications RNA Research Risk Risk Factors Role Sampling Serum Site Smoking Source Subtilisins Testing Tobago Universities Variant Vascular calcification Visit WNT Signaling Pathway X-Ray Computed Tomography aged aortic arch arterial remodeling base calcification cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor carotid intima-media thickness cohort coronary artery calcification ethnic difference health care availability health goals hemodynamics high risk improved indexing men mortality novel novel marker peripheral blood personalized care programs protein expression racial and ethnic racial difference receptor recruit repository

项目摘要

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death worldwide and the global burden of CVD has accelerated the need to better understand its epidemiology, identification, and treatment, particularly in high-risk and understudied population groups. African ancestry individuals have a higher risk of CVD events and mortality compared to European ancestry individuals and, although mechanisms for the racial differences in CVD are complex, it is clear that molecular and genetic differences play an important role. Emerging evidence indicates that the Wingless (Wnt) signaling pathway plays a role in CVD; however, there has been limited research on this role in humans. The funded K01 award (HL-125658 PI: Kuipers) aims to comprehensively investigate this relationship by leveraging data from a unique longitudinal cohort study of African ancestry men aged ≥40 years – the Tobago Health Study (THS), which has been ongoing since 1997. The K01 research is the first study of CVD in the THS and has recruited and collected data on 421 African ancestry men. Data collected for the K01 study include: serum and RNA samples, and multiple measures of subclinical CVD, including carotid intima- media thickness and diameter, pulse-wave velocity, ankle-brachial index, and coronary and aortic calcification. Part of the recruitment was targeted to include THS men known to carry a functional, African ancestry-specific missense variant (Ala64Thr) in the Wnt receptor, Frizzled-1 (FZD1) gene. In in vitro studies, this variant leads to over-activation of the Wnt pathway and the Hypothesis was that carriers of the variant would have a greater burden of subclinical CVD compared to non-carriers. Indeed, carriers (N=64) have larger carotid diameter than non-carriers, even after adjusting for age and other traditional cardiovascular risk factors. Thus, THS men with more Wnt activation appear to show greater outward arterial remodeling than men with usual Wnt function. In the current study, we will further investigate Wnt’s role in arterial remodeling by assessing a newly identified subclinical CVD marker thought to be reflective of early arterial changes: aortic diameter. Aortic diameter and cross sectional area will be assessed at multiple sites along the length of the aorta using archived computed tomography images from the THS study. These data will be used to test the hypothesis that changes in aortic diameter reflect the earliest measurable subclinical vascular changes compared to other established subclinical CVD markers. In addition, these data will further refine the vascular location of Wnt pathway function. Lastly, since CVD is a new focus of the THS, there are no data on cardiovascular biomarkers in the cohort, which is a big limitation for following-up on the molecular underpinnings of subclinical CVD in manuscripts or funding proposals. Therefore, a state-of-the-art, microfluidic assay (O-Link: “CVDIII” panel) will be used to measure 92 pre-determined serum CV biomarkers. These represent both established and novel CVD biomarkers and will be used as critical covariates in the planned K01 study analyses, as well as, a source for hypothesis generation on novel biomarkers of subclinical CVD in this high-risk, but understudied, African ancestry cohort.

项目概要心血管疾病（CVD）是全世界死亡的主要原因，CVD 的全球负担已加速了更好地了解其流行病学、识别和治疗的需要，特别是在高风险地区和未得到充分研究的人群中，非洲血统的人发生心血管疾病和死亡的风险较高。与欧洲血统个体相比，尽管 CVD 种族差异的机制尚不明确尽管情况复杂，但新出现的证据表明分子和遗传差异发挥着重要作用。 Wingless (Wnt) 信号通路在 CVD 中发挥作用，但对此的研究还很有限；资助的 K01 奖（HL-125658 PI：Kuipers）旨在全面研究这一点。利用针对 40 岁以上非洲血统男性的独特纵向队列研究的数据来确定关系 – 多巴哥健康研究 (THS)，自 1997 年以来一直在进行。K01 研究是第一项研究 THS 中的 CVD 已招募并收集了 421 名非洲血统男性的数据为 K01 收集的数据。研究包括：血清和 RNA 样本，以及亚临床 CVD 的多项测量，包括颈动脉内膜中膜厚度和直径、脉搏波速度、踝肱指数以及冠状动脉和主动脉钙化。部分招募的目标是包括已知具有功能性、非洲血统的 THS 男性 Wnt 受体、Frizzled-1 (FZD1) 基因中的错义变异 (Ala64Thr) 在体外研究中，该变异导致。 Wnt 通路过度激活，并且假设该变异的携带者将具有更大的与非携带者相比，亚临床 CVD 的负担确实，携带者 (N=64) 的颈动脉直径比非携带者更大。即使在调整了年龄和其他传统心血管危险因素之后，非携带者也患有 THS 男性。与具有正常 Wnt 功能的男性相比，更多的 Wnt 激活似乎表现出更大的向外动脉重塑。在当前的研究中，我们将通过评估新发现的一种新方法来进一步研究 Wnt 在动脉重塑中的作用亚临床 CVD 标志物被认为反映了早期动脉变化：主动脉直径。将使用存档的计算数据在沿主动脉长度的多个部位评估横截面积 THS 研究中的断层扫描图像将用于检验主动脉变化的假设。与其他已建立的亚临床血管变化相比，直径反映了最早可测量的亚临床血管变化此外，这些数据将进一步细化Wnt通路功能的血管定位。由于 CVD 是 THS 的新焦点，因此该队列中没有心血管生物标志物的数据，这是一个手稿或资金对亚临床 CVD 分子基础的后续研究存在很大限制因此，将使用最先进的微流体测定（O-Link：“CVDIII”面板）来测量 92 预先确定的血清 CV 生物标志物这些代表了已建立的和新的 CVD 生物标志物，并且将成为新的 CVD 生物标志物。用作计划的 K01 研究分析中的关键协变量，以及假设生成的来源在这个高风险但尚未得到充分研究的非洲血统队列中，发现了亚临床心血管疾病的新生物标志物。