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

• 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
• 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

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.

项目摘要 心血管疾病（CVD）是全球死亡的主要原因，CVD的全球燃烧已有 加速了更好地了解其流行病学，识别和治疗的需求，尤其是在高风险中 并了解人口群体。非洲血统的人患CVD事件和死亡率的风险更高 与欧洲血统个人相比，尽管CVD种族差异的机制是 复杂，很明显，分子和遗传差异起着重要作用。新兴证据表明 无翼（Wnt）信号通路在CVD中起作用；但是，对此有限 在人类中的作用。资助的K01奖（HL-125658 PI：Kuipers）旨在全面调查此事 通过利用≥40岁的非洲血统男性的独特纵向队列研究的数据来利用数据 - 自1997年以来一直在进行的Tobago Health研究（THS）。K01研究是首次研究 CVD在THS中，已招募并收集了421名非洲血统男子的数据。为K01收集的数据 研究包括：血清和RNA样品以及亚临床CVD的多种度量，包括颈动脉内膜 培养基厚度和直径，脉冲波速度，脚踝 - 桥梁指数以及冠状动脉和主动脉钙化。 该招聘的一部分针对的是包括携带功能性的非洲血统特定的人 Wnt受体中的错义变体（ALA64THR），Frizzled-1（FZD1）基因。体外研究，这种变体导致 Wnt途径的过度激活和假设是该变体的载体将具有更大的 与非携带者相比，亚临床CVD的负担。确实，载体（n = 64）的颈动脉直径大于 非携带者，即使在调整了年龄和其他传统的心血管危险因素之后。那是男人 比具有常规Wnt功能的男性，更大的Wnt激活外观显示出更大的外部动脉重塑。在 当前的研究，我们将通过评估新鉴定 亚临床CVD标记被认为反映了早期动脉变化：主动脉直径。主动脉直径和 将使用存档的计算 THS研究中的断层扫描图像。这些数据将用于检验主动脉变化的假设 直径反映了与其他已建立的亚临床的最早可测量亚临床血管变化 CVD标记。另外，这些数据将进一步完善Wnt途径功能的血管位置。最后， 由于CVD是THS的新焦点，因此在同类中没有关于心血管生物标志物的数据，这是 在手稿或资金中跟踪亚临床CVD的分子基础的最大限制 建议。因此，将使用最先进的微流体测定法（O-Link：“ CVDIII”面板）测量92 预定的血清简历生物标志物。这些代表建立和新颖的CVD生物标志物，将是 在计划的K01研究分析中用作关键协变量，也用作假设产生的来源 在这个高风险中，但被理解为非洲血统队列中的亚临床CVD的新型生物标志物。