Genetic Variations in the HPA Axis and Comorbidity of Depression and Cardiovascul

描述(申请人提供)：心血管疾病(CVD)和抑郁症是两种复杂的疾病，经常同时发生。然而，将抑郁症和心血管疾病联系起来的潜在机制仍不清楚。最近的研究表明，共同的遗传易感性可能解释了这两种疾病的共病。由于在人类和动物模型中的研究一致地报道了下丘脑-垂体-肾上腺(HPA)轴功能障碍在抑郁症和CVD风险中的作用，因此HPA系统的遗传异常可能是导致抑郁症和CVD并存的重要病理生理机制。该项目的总体目标是检验这一假设，即HPA相关通路中的遗传变异是抑郁症和心血管疾病易感性的关键决定因素。我们将使用一对双胞胎样本，包括越南时代双胞胎登记处(VETR)的640对中年男性双胞胎，对涉及HPA轴和相关途径的19个关键候选基因进行分型。在最近的研究中，所有这些双胞胎都被广泛地分型，包括关于抑郁症状、亚临床心血管疾病、压力和其他心理变量的详细测量，以及行为和社会人口变量的信息。这项使用双胞胎的拟议研究提供了一个独特的机会，可以梳理出在经典遗传学研究中通常被其他因素混淆的基因环境影响。这项研究的发现不仅可能为揭示这两种常见疾病的潜在机制打开新的窗口，而且在未来还可能为最佳治疗方法提供指导，特别是对遗传易感个体。公共卫生相关性：这项研究建议使用来自越南时代双胞胎登记处的表型良好的双胞胎数据库，确定HPA轴上常见的基因多态和相关的生物学途径，以导致抑郁症和心血管疾病的共病。研究结果将为破译心血管和精神疾病的遗传基础提供有价值的数据。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) and depression are two complex diseases that often co-occur. However, the potential mechanisms linking depression and CVD remain unclear. Recent studies suggest that common genetic vulnerability may explain the comorbidity of these two disorders. Because studies in human and animal models have consistently reported the role of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in the risk of both depression and CVD, genetic abnormalities in the HPA system may thus represent an important pathophysiological mechanism that contributes to the co-occurrence of depression and CVD. The overall objective of this project is to test the hypothesis that genetic variants within the HPA-related pathways are key determinants for the vulnerability to both depression and CVD. We will genotype 19 key candidate genes involved in the HPA axis and related pathways using a twin sample including 640 middle-aged male twins from the Vietnam Era Twin Registry (VETR). All these twins were extensively phenotyped in recent studies, including information on depressive symptoms, subclinical CVD, detailed measurements of stress and other psychological variables, as well as behavioral and social-demographic variables. The proposed study using twins provides a unique opportunity to tease out gene-environment effects that are usually confounded by other factors in classical genetic studies. Findings from this study may not only open new windows into the mechanisms underlying these two common disorders but in the future may also provide guidance for optimal therapeutic treatments particularly for genetically susceptible individuals. PUBLIC HEALTH RELEVANCE: This study proposes to identify common genetic polymorphisms in the HPA axis and related biological pathways for the comorbidity of depression and cardiovascular disease using a well-phenotyped twin database from the Vietnam Era Twin Registry. Results will provide valuable data for deciphering the genetic basis of cardiovascular and psychiatric diseases.