Physical Frailty in Urban African-Americans

描述（由申请人提供）：这份城市非洲裔美国人身体虚弱的NIH修订申请（PFUAA; AG10436）响应PAR-08-065。它要求提供3年的资金，以便对居住在密苏里州圣路易斯市的具有代表性的具有良好特征的非裔美国人队列进行额外的数据收集（非裔美国人健康项目，或AAH）。使用单SNP/单倍型关联分析，收集有关遗传因素和抑郁在介导AAH患者冠状动脉疾病（CAD）风险中的潜在相互作用的数据。冠心病是美国心血管疾病发病率和死亡率的主要原因。在全国范围内，非裔美国人冠心病的发病率和死亡率高于白人，尤其是在密苏里州和圣路易斯市。抑郁症也很常见，并且与CAD有多种不良关联。在以人群为基础的样本中，尤其是在非裔美国人中，这些关系还没有得到充分的研究。由于虚弱和残疾与动脉粥样硬化疾病和抑郁症状都相关，因此更好地了解cad -抑郁不良关联的遗传原因对AAH项目至关重要。先前的数据表明，这些情况在AAH中很常见，心血管疾病的3年患病率为42%，临床相关抑郁症状的3年患病率为31%。尽管众所周知的cad与抑郁症的不良关联，但精确的遗传因素和介导它们的分子机制在很大程度上仍然未知。该项目的首要假设是，抑郁症通过共同基因-基因（GXG）和/或基因-环境（GXE）相互作用促进CAD的发展和后遗症。为了检验这一假设，NIH修订项目将招募450名AAH受试者，以实现三个具体目标：在社区居住的57-75岁非裔美国人中确定CAD和抑郁表型的患病率。SA2。研究这一人群中CAD和抑郁表型之间的关系，强调选定基因在血清素和炎症途径中的调节作用。SA3。发现潜在的基因-抑郁相互作用对非裔美国人CAD的发展有重要贡献。我们已经组建了一支优秀的多学科团队，拥有开展这项研究所需的所有专业知识，包括流行病学（衰老、抑郁、心血管和遗传）、心脏成像、CAD和抑郁症表型、心血管疾病突变分析，以及（至关重要的）开发和使用新的统计方法来研究心血管疾病的遗传多态性转化研究。我们计划在这个项目之后申请更大的拨款，以招募1050名额外的受试者，并进行全基因组分析，以更深入地解决这些重要问题。这项研究有潜力为药物和非药物方法确定极好的靶点，以预防、改善或逆转这些重要疾病中的一种或两种。公共卫生相关性：冠状动脉疾病是美国死亡和健康问题的主要原因，对非洲裔美国人的影响尤其严重。无论是黑人还是白人，抑郁的存在都会增加冠状动脉疾病及其所有并发症的发生频率。本研究的目的是在一项对生活在密苏里州圣路易斯的非裔美国人进行的研究中检查冠状动脉疾病和抑郁症之间的关系，重点是了解遗传因素如何与抑郁症状相互作用，从而对冠状动脉疾病产生如此强烈的负面影响。

DESCRIPTION (provided by applicant): This NIH Revision application for Physical Frailty in Urban African Americans (PFUAA; AG10436) responds to PAR-08-065. It requests 3 years of funding to enable additional data collection on a representative well-characterized cohort of African Americans living in St. Louis, MO, (the African American Health project, or AAH). Data to be collected relate to potential interactions between genetic factors and depression in mediating coronary artery disease (CAD) risk in AAH using single SNP/haplotype association analyses. CAD is the leading cause of cardiovascular morbidity and mortality in the U.S. Nationally, African Americans have higher morbidity-mortality rates from CAD than whites, and particularly so in Missouri and in the city of St. Louis. Depression is also common and has multiple adverse associations with CAD. These relationships have been understudied in population-based samples and especially in African Americans. As frailty and disability are associated with both atherosclerotic disease and depressive symptoms, better understanding of the genetic reasons for the adverse CAD-depression associations is crucial to the AAH project. Prior data indicate that these conditions are common in AAH, with 3-year period prevalences of 42% for cardiovascular diseases and 31% for clinically relevant levels of depressive symptoms. Despite the well-known CAD-depression adverse associations, the precise genetic factors and molecular mechanisms mediating them remain largely unknown. The overarching hypothesis of this project is that depression contributes to the development and sequelae of CAD through common gene-gene (GXG) and/or gene-environment (GXE) interactions. To examine this hypothesis, this NIH Revision project will enroll 450 AAH subjects to pursue three specific aims: SA1. Identify the prevalence of CAD and depression phenotypes in a population-based sample of community-dwelling 57-75 year old African Americans. SA2. Examine the relationships between the CAD and depression phenotypes in this population, highlighting the modulating role of selected genes in the serotonin and inflammatory pathways. SA3. Discover potential gene-depression interactions with significant contribution to the development of CAD in African Americans. We have assembled an outstanding multidisciplinary group with all the required expertise to conduct this research, including epidemiology (aging, depression, cardiovascular, and genetic), cardiac imaging, CAD and depression phenotyping, cardiovascular disease mutation analysis, and (crucially) the development and use of novel statistical methods to study genetic polymorphisms for translational studies of cardiovascular disease. We plan to follow this project with a larger grant application to recruit 1050 additional subjects and perform genome wide analyses to address these important issues in even greater depth. This research has the potential to identify excellent targets for pharmacological and non-pharmacological approaches to preventing, ameliorating, or reversing either or both of these important conditions. PUBLIC HEALTH RELEVANCE: Coronary artery disease is a leading cause of death and health problems in the U.S. and has a particularly strong impact on African Americans. The presence of depression increases the frequency of coronary artery disease and all its complications in both blacks and whites. The purpose of this research is to examine the relationship between coronary artery disease and depression in an ongoing study of African Americans living in St. Louis, Missouri with an emphasis on understanding how genetic factors interact with depression symptoms to exert such a strong negative impact on coronary artery disease.