Stress, Gene-Environment Interaction and Cardiovascular Disease

描述（由研究者提供）：尽管心理社会应激被假设在心血管疾病的病因学中起作用，但对应激作用和应激作用的生物学机制的经验验证仍然很少。一个主要的局限性是缺乏对压力进行直接生物测量的人口研究（例如测量压力激素水平），因此可以研究它们与社会前因和心血管疾病生物前兆的联系。越来越明显的是，社会条件和压力源必须与基因组成相互作用，其中一些暴露可能通过DNA甲基化的变化来改变基因表达，但很少有人口研究全面调查了与心理社会因素相关的基因-环境相互作用和表观遗传变化。该项目的一个主要目标是更好地了解社会模式压力与遗传学和生物学相互作用的方式，以影响心血管相关的结果。使用来自动脉粥样硬化多种族研究的数据，一个大的，多种族的人口样本，我们建议调查长期协会的压力反应（特点是多种措施的压力激素）与社会/心理社会的前因和心血管相关的结果，以及修改的压力反应的变化，在选定的候选基因，和社会心理因素和表观遗传变化之间的联系。该项目的具体目标是：（1）研究应激激素重复测量与社会和心理社会因素以及与心血管疾病的生物学前兆（包括炎症/止血和胰岛素抵抗和肥胖的测量）之间的关联;（2）研究皮质醇水平和糖皮质激素受体基因多态性之间的相互作用与心血管相关结果;（3）研究生物学相关基因多态性改变对心理应激挑战的反应的程度;（4）研究表观遗传变化糖皮质激素受体基因（DNA甲基化）以及基因组DNA甲基化及其与（a）生活过程社会暴露;（B）皮质醇和对应激挑战的血流动力学反应;和（c）以前与压力暴露有关的生物参数。我们的研究不仅将增强我们对压力和心血管疾病之间流行病学联系的理解，还将增强我们对这些影响可能介导的生物学机制（涉及遗传多态性和基因表达变化）的理解。通过说明遗传变异性，生物标志物和社会条件的研究如何整合，以提高我们对健康不良原因的理解，我们的项目有可能为健康研究的重大范式变化做出贡献。 公共卫生相关性：有人认为，压力可能对心血管疾病的发展很重要，但很少有人口研究全面调查了压力的运作方式。这项研究将调查压力和心血管疾病重要的生物因素之间的联系，包括压力和基因之间的相互作用。这种方法对于更好地理解压力的重要性和制定预防性干预措施是必要的。

DESCRIPTION (provided by investigator): Although psychosocial stress has been hypothesized to play a role in the etiology of cardiovascular disease, empirical verifications of the effects of stress and the biological mechanisms through which stress operates remain rare. A major limitation has been the absence of population studies with direct biologic measures of stress (such as measures of levels of stress hormones), so that their link to social antecedents and to biological precursors of cardiovascular disease can be studied. It has also become increasingly apparent that social conditions and stressors must interact with genetic makeup, and that some of these exposures may modify gene expression through changes in DNA methylation but few population studies have comprehensively investigated the gene-environment interactions and epigenetic changes related to psychosocial factors. A major goal of this project is to better understand the ways in which socially patterned stress interacts with genetics and biology to influence cardiovascular-related outcomes. Using data from the Multiethnic Study of Atherosclerosis, a large, multiethnic population sample, we propose to investigate long-term associations of the stress response (as characterized by multiple measures of stress hormones) with social/psychosocial antecedents and cardiovascular-related outcomes, as well as modifications of the stress response by variations in selected candidate genes, and links between psychosocial factors and epigenetic changes. The Specific Aims of the project are: (1) To examine associations of repeat measures of stress hormones with social and psychosocial factors and with biological precursors of cardiovascular disease including inflammation/hemostasis and measures of insulin resistance and adiposity; (2) To examine interactions between cortisol levels and polymorphisms of the glucocorticoid receptor gene with respect to cardiovascular-related outcomes; (3) To examine the extent to which polymorphisms of biologically relevant genes modify the response to a psychological stress challenge; and (4) To examine epigenetic changes (DNA methylation) of the glucocorticoid receptor gene as well as genomic DNA methylation and their association with (a) lifecourse social exposures; (b) cortisol and hemodynamic responses to a stress challenge; and (c) biological parameters previously linked to stress exposures. Our study will enhance our understanding not only of the epidemiologic links between stress and cardiovascular disease but also of the biologic mechanisms (involving genetic polymorphisms and changes to gene expression) through which these effects may be mediated. By illustrating how the study of genetic variability, biological markers, and social conditions can be integrated to enhance our understanding of the causes of ill health our project has the potential for contributing to major paradigmatic change in health research. PUBLIC HEALTH RELEVANCE: It has been argued that stress may be important to the development of cardiovascular disease, but few population studies have comprehensively investigated the way in which stress operates. This study will investigate the links between stress and biological factors important to cardiovascular disease, including the interactions between stress and genes. This approach is necessary to better understand the importance of stress and to develop preventative interventions.