Depression, inflammation, and diabetes: Exploring shared etiopathology

描述（由申请人提供）：流行病学和临床研究已证实，重度抑郁症 (MD) 经常与晚年的健康状况同时发生，包括代谢性疾病，如 2 型糖尿病（以下简称“糖尿病”）。现在人们承认MD和糖尿病之间的相互关系可能是双向的。事实上，基于人群的队列研究一致的证据表明，MD 与糖尿病和心血管疾病的风险和死亡率增加有关。然而，前瞻性研究无法明确区分MD是否是代谢紊乱的独特危险因素，或者这种现象是否是由于MD和糖尿病共有的共同因素造成的，例如遗传倾向、环境压力或全身生理失调。功能基因组学，特别是基因表达的评估，提供了一种新的方法来指定环境暴露如何与影响生理学的遗传倾向相交叉。该职业发展奖 (K01) 的广泛目标是调查同时发生的 MD 和糖尿病之间的病因关系，特别是遗传和环境风险来源的结构和相对贡献。这项研究利用互补方法来研究以下目标：首先，将使用潜变量双胞胎模型来检查这种合并症背后的广泛遗传和环境途径；其次，基因表达阵列将用于检查抑郁症状影响糖尿病风险的特定生物学途径。该研究计划的具体目标是：1）评估环境和遗传因素及其相互作用对成年后期MD与糖尿病之间关系的影响； 2）研究MD和糖尿病之间的行为途径，同时考虑到共同的遗传责任； 3）检查抑郁症状与免疫相关基因表达之间的关系。候选人将接受负责任的研究、遗传流行病学和功能基因组学方面的培训。候选人提议在精神病学、免疫学、功能基因组学、流行病学和生物统计学专家的密切指导培训期间实施这项研究计划。拟议的培训计划将促进她向独立的流行病学家过渡，专注于探索心理健康的心理、行为、生物和遗传方面的综合模型。该研究计划针对严重抑郁症和糖尿病这两种常见且令人衰弱的健康状况的交叉点，这两种疾病是美国和全球医疗保健成本和公共卫生负担的主要来源。这项研究的公共卫生意义集中在了解精神和身体健康之间的病因关系，以便制定全面的计划来改善精神疾病患者的健康。 公共卫生相关性：本应用程序的目标是利用来自两个基于人群的队列和一项遗传信息双胞胎研究的补充数据来调查同时发生的 MD 和糖尿病的病因学性质。目的是： 1) 评估环境和遗传因素及其相互作用对成年后期 MD 和糖尿病之间关系的影响； 2）研究MD和糖尿病之间的行为途径，同时考虑到共同的遗传责任； 3）检查抑郁症状对免疫相关基因表达的影响。这项研究的意义在于了解心理和身体健康之间的病因关系，以改善精神疾病患者的健康。

DESCRIPTION (provided by applicant): Epidemiologic and clinical studies have established that Major Depression (MD) often co-occurs with medical conditions in later life, including metabolic disorders such as Type 2 Diabetes Mellitus (hereafter referred to as 'Diabetes'). It is now acknowledged that the inter-relationship between MD and Diabetes is likely bi-directional. Indeed, there is consistent evidence from population-based cohort studies that MD is associated with increased risk of and mortality from Diabetes and cardiovascular disease. However, prospective studies cannot definitively distinguish whether MD is a unique risk factor for metabolic disorders, or if this phenomenon is due to a common factor shared by both MD and Diabetes such as genetic liability, environmental stress, or systemic physiologic deregulation. Functional genomics, particularly assessment of gene expression, offer a novel means of specifying how environmental exposures intersect with genetic liability to influence physiology. The broad objective of this Career Development Award (K01) is to investigate the etiologic relationships between co-occurring MD and Diabetes, in particular the structural and relative contributions of genetic and environmental sources of risk. This research utilizes complementary approaches to investigating the aims below: first, the broad genetic and environmental pathways underlying this comorbidity will be examined using latent variable twin modeling; second, gene expression arrays will be used to examine specific biological pathways by which depressive symptoms influence Diabetes risk. The specific aims of the research plan are to: 1) evaluate environmental and genetic contributions, and their interaction, of the relationship between MD and Diabetes in later adulthood; 2) investigate the behavioral pathways linking MD and Diabetes while accounting for shared genetic liability; and 3) examine the relationship between depressive symptoms and expression of immune-related genes. The candidate will receive training in responsible conduct of research, genetic epidemiology, and functional genomics. The candidate proposes to implement this research plan during a period of closely mentored training with experts in psychiatry, immunology, functional genomics, epidemiology, and biostatistics. The proposed training plan will promote her transition to independence as an epidemiologist focused on exploring an integrative model of the psychological, behavioral, biological, and genetic aspects of mental health. The research plan addresses the intersection of two common and debilitating health conditions, Major Depression and Diabetes, that are leading sources of healthcare costs and public health burden in the US and globally. The public health significance of this research centers on understanding the etiologic relationships between mental and physical health in order to develop comprehensive programs to improve the health of persons with psychiatric disorders. PUBLIC HEALTH RELEVANCE: The goal of this application is to investigate the etiologic nature of co-occurring MD and Diabetes using complementary data from two population-based cohorts and a genetically informative twin study. The aims are to: 1) evaluate environmental and genetic contributions, and their interaction, of the relationship between MD and Diabetes in later adulthood; 2) investigate the behavioral pathways linking MD and Diabetes while accounting for shared genetic liability; and 3) examine the influence of depressive symptoms on expression of immune-related genes. The significance of this research centers on understanding the etiologic relationships between mental and physical health to improve the health of persons with psychiatric disorders.