Molecular Epidemiology of the Wnt Pathway in Subclinical Cardiovascular Disease

 描述（由申请人提供）：心血管疾病（CVD）是全球死亡的主要原因，其中80%以上的死亡发生在低收入和中等收入国家。CVD的全球负担加速了更好地了解其流行病学，识别和治疗的需要，特别是在高风险和研究不足的人群中。与欧洲血统的个体相比，非洲血统的个体具有更高的CVD事件和死亡率风险，并且这种种族/民族差异不能用传统的CVD风险因素或单独获得医疗保健来解释。虽然CVD流行病学中种族差异的机制是复杂的和多因素的，但很明显，易感性的分子和遗传差异起着重要作用。主要来自动物模型和体外实验的新证据表明，无翅（Wnt）信号通路在血管生成、血管钙化和动脉粥样硬化中起作用。然而，对Wnt信号通路在人类CVD中的作用知之甚少。此外，人类研究仅关注Wnt相关蛋白的有限子集，尚未评估CVD中Wnt信号通路的其他关键组分。我们的初步数据显示，与野生型基因型（Ala 64 Ala）相比，Wnt辅助受体Frizzled-1（FZD 1）中具有功能性和种族特异性错义变体（Ala 64 Thr）的非洲血统男性和女性的颈动脉超声内膜中层厚度更大。为了更全面地量化Wnt通路与人类亚临床CVD之间的关联，我们将利用我们对年龄≥ 40岁的非洲血统男性进行的大型、正在进行的队列研究的数据。我们目前正在对1200名非洲血统男性进行腹部和胸部CT扫描，以研究异位肥胖和糖尿病。在这项研究中，我们还获得和存档的图像颈动脉超声和臂踝脉搏波速度。这些数据将构成本提案的目的的基础，即量化365名非洲血统男性中Wnt通路基因和蛋白表达的血液水平与亚临床CVD测量值之间的关联，亚临床CVD测量值包括冠状动脉和主动脉钙化、颈总动脉内膜-中层厚度和外膜直径、臂踝脉搏波速度和踝臂指数。我们还将进行基因型定向招募100名FZD 1基因已知功能变异的男性，并测试变异携带者和非携带者对照之间亚临床CVD指标的差异，这些变异携带者和非携带者对照将从一般研究人群中招募。这些研究目标的成功完成，沿着强化培训和指导计划，将为申请人提供五个主要领域的新技能和“动手”培训：流行病学现场研究，更深入的亚临床CVD表型，心血管生理学培训，分子流行病学实验室培训和培训。该职业发展奖将为申请人提供受保护的时间进行教学培训和新技能的开发，这将为亚临床CVD分子流行病学的独立研究生涯奠定基础。

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death worldwide and more than 80% of these deaths occur in low- and middle-income countries. 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 this racial/ethnic difference is not explained by traditional CVD risk factors or access to healthcare alone. Although mechanisms for the race differences in CVD epidemiology are complex and multifactorial, it is clear that molecular and genetic differences in susceptibility play an important role. Emerging evidence, primarily from animal models and in vitro experiments, indicates that the Wingless (Wnt) signaling pathway plays a role in angiogenesis, vascular calcification, and atherosclerosis. However, less is known about the role of the Wnt signaling pathway in CVD in humans. In addition, human studies have focused on only a limited subset of Wnt related proteins and have not assessed other key components of the Wnt signaling pathway in CVD. Our preliminary data in African ancestry men and women with a functional and race specific missense variant (Ala64Thr) in the Wnt co-receptor, Frizzled-1 (FZD1), revealed greater carotid ultrasound intima-media thickness compared to those with the wild-type genotype (Ala64Ala). In order to more comprehensively quantify the association between the Wnt pathway and subclinical CVD in humans, we will utilize data from our large, ongoing cohort study of African ancestry men aged =40 years. We are currently performing abdominal and chest CT scans for a study of ectopic adiposity and diabetes in 1200 African ancestry men. During this study, we are also obtaining and archiving images of carotid artery ultrasound and brachial-ankle pulse-wave velocity. These data will form the basis of the Aims of this proposal, which are to quantify the association between blood levels of Wnt pathway gene and protein expression with measures of subclinical CVD including coronary and aortic artery calcification, common carotid intima-media thickness and adventitial diameter, brachial-ankle pulse-wave velocity and ankle-brachial index in 365 men of African ancestry. We will also perform genotype-directed recruitment of 100 men with a known functional variant in the FZD1 gene and test for a difference in measures of subclinical CVD between variant carriers and non-carrier controls that will be recruited from the general study population. The successful completion of these research aims, along with an intensive training and mentorship plan, will provide the applicant with new skills and "hands-on" training in five major areas: epidemiologic field research, deeper subclinical CVD phenotyping, and training in cardiovascular physiology, molecular epidemiology laboratory training and grantsmanship. This Career Development Award will provide the applicant with protected time for didactic training and development of new skills that will lay the foundation for an independent research career in the molecular epidemiology of subclinical CVD.