Molecular Epidemiology of Aortic Diameter and Subclinical Cardiovascular Disease

项目总结 心血管疾病(CVD)是世界范围内主要的死亡原因，全球范围内的心血管疾病负担 加速了更好地了解其流行病学、识别和治疗的必要性，特别是在高危人群中 以及未被充分研究的人口群体。非洲血统的人发生心血管疾病和死亡的风险更高 与欧洲血统相比，尽管心血管疾病种族差异的机制是 复杂性，很明显，分子和遗传差异起着重要作用。新出现的证据表明 无翼(Wnt)信号通路在心血管疾病中的作用；然而，对此的研究有限 在人类身上的角色。基金K01奖(HL-125658 PI：Kuipers)旨在全面调查这一点 通过利用来自一项对年龄为≥40岁的非洲血统男性的独特纵向队列研究的数据来确定两人之间的关系 -自1997年以来一直在进行的多巴哥健康研究。K01研究是第一个关于 该中心还在THS招募和收集了421名非洲裔男子的数据。为K01收集的数据 研究包括：血清和RNA样本，以及亚临床心血管疾病的多种测量，包括颈动脉内膜- 中层厚度和直径、脉搏波速度、踝臂指数、冠状动脉和主动脉钙化。 招募的一部分目标是包括已知携带功能性非洲血统的THS男性 Wnt受体Frizzled1基因错义突变(Ala64Thr)。在体外研究中，这种变异导致 Wnt途径的过度激活，并且假设该变体的携带者将有更大的 与非携带者相比，亚临床脑血管病的负担。事实上，携带者(N=)的颈动脉直径比 非携带者，即使在调整了年龄和其他传统的心血管风险因素后也是如此。因此，患有THS的男性 与正常WNT功能的男性相比，更多的WNT激活似乎显示出更大的外向动脉重构。在……里面 在目前的研究中，我们将通过评估新发现的WNT在动脉重构中的作用来进一步研究WNT在动脉重构中的作用 被认为能反映早期动脉变化的亚临床CVD标记物：主动脉直径。主动脉内径和 将使用存档的计算机在沿主动脉长度的多个位置评估横截面面积 来自THS研究的断层扫描图像。这些数据将被用来检验这样的假设，即主动脉的变化 直径反映了与其他已建立的亚临床相比最早可测量的亚临床血管变化 心血管疾病标志物。此外，这些数据还将进一步完善Wnt通路功能的血管定位。最后， 由于心血管疾病是THS的新焦点，因此在队列中没有关于心血管生物标志物的数据，这是一种 在论文或基金中对亚临床脑血管病的分子基础进行随访的很大限制 提案。因此，将使用最先进的微流控分析(O-Link：“CVDIII”面板)来测量92 预先确定的血清CV生物标志物。这些既是已建立的和新的心血管生物标志物，也将是 在计划中的K01研究分析中用作关键协变量，也是假设生成的来源 亚临床脑血管病的新生物标志物在这一高风险但未被充分研究的非洲血统队列中。

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.