Stress, Gene-Environment Interaction and Cardiovascular Disease

描述（由研究者提供）：尽管社会心理压力已被假设在心血管疾病的病因中发挥作用，但对压力影响和压力作用的生物学机制的经验验证仍然很少。一个主要的限制是缺乏对压力进行直接的生物学测量的人口研究（例如对压力激素水平的测量），因此可以研究它们与社会前因和心血管疾病的生物前体的联系。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基因-环境相互作用和与社会心理因素相关的表观遗传变化。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和生物学相互作用的方式，从而影响心血管相关的结果。利用来自多民族动脉粥样硬化研究的数据，我们建议研究压力反应（以多种压力激素测量为特征）与社会/心理社会因素和心血管相关结果的长期关联，以及选择的候选基因变异对压力反应的改变，以及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)检查应激激素的重复测量与社会和社会心理因素以及心血管疾病的生物前兆（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与心血管相关结局之间的相互作用；(3)研究生物相关基因的多态性在多大程度上改变了对心理压力挑战的反应；(4)研究糖皮质激素受体基因的表观遗传变化（DNA甲基化）以及基因组DNA甲基化及其与(a)生命周期社会暴露的关系；(b)应激刺激下的皮质醇和血流动力学反应；(c)先前与压力暴露有关的生物学参数。我们的研究不仅将加深我们对压力和心血管疾病之间的流行病学联系的理解，而且还将加深我们对这些影响可能介导的生物学机制（包括遗传多态性和基因表达的变化）的理解。通过说明如何将遗传变异、生物标记和社会条件的研究整合起来，以增强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。

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.