Social disadvantage and immune gene expression in an urban US population

项目总结 社会逆境是健康状况不佳、疾病易感性增加和 在美国寿命较短。最近在实验动物模型中的研究表明，这些 关系不能完全用健康危险行为或健康选择来解释，免疫系统的变化 基因调控也起到了一定作用。有趣的是，许多受社会逆境影响的生物途径 动物模型也与人类的社会逆境有关。然而，到目前为止，大多数针对人类的研究 已经专注于临床或机会性收集的样本，还没有人调查过社会 不利影响基因表达对环境挑战的反应，如病原体感染， 这可能会进一步放大社会环境影响。 拟议研究的目标是通过利用独特的人口-- 底特律社区健康研究(DNHS)收集的底特律代表性样本。国土安全部 将广泛的社区和个人层面的社会劣势数据与基因数据结合起来， 至关重要的是，来自同一研究对象的冷冻保存的外周血单个核细胞(PBMC)的生物库。 我将利用这些资源来解决三个问题。首先，社会劣势会对多个国家产生什么影响 措施，对人类免疫基因表达基线有影响吗？这一目标将扩大对社会逆境的研究 和免疫基因表达对美国城市人口的影响，其中多种类型的 可以评估社会逆境(例如，社会经济地位低、最近的创伤、邻里水平的贫困)。 第二，基因在多大程度上调节社会环境对免疫基因调控的影响？ 这一分析将强调遗传差异是否对形成对社会逆境的敏感性很重要， 以免疫基因表达为模型。第三，社会劣势会在多大程度上影响免疫力 对病毒挑战(巨细胞病毒和爱泼斯坦-巴尔病毒)的反应已被证明遵循社会 在这个人口中存在梯度吗？这一分析将提供对社会劣势是否与 免疫功能的差异通过评估基因表达而导致病毒感染的社会梯度 从DNHS研究对象收集的原代PBMC对体外病毒挑战的反应。 这些分析将提供对社会逆境在塑造整个社会的免疫功能方面的作用的洞察 美国的一系列社会劣势。拟议中的工作既将增加关于社会问题的日益增长的文献 人类的逆境和基因表达，并阐明了基因和病原体环境在 在这种关系中制造了异质性。它还将从Function和 统计基因组学(细胞培养中的表达、数量性状基因座定位和体外挑战) 健康中的社会梯度研究。因此，通过这样做，它不仅代表着一种宝贵的培训经验 但将为更普遍的社会逆境的生物社会学研究提供一个广泛适用的模型。

PROJECT SUMMARY Social adversity is one of the most robust predictors of poor health, increased disease susceptibility, and shorter lifespan in the United States. Recent work in experimental animal models suggests that these relationships cannot be fully explained by health risk behaviors or health selection, and that changes in immune gene regulation also play a role. Intriguingly, many of the biological pathways affected by social adversity in animal models are also correlated with social adversity in humans. To date, however, most studies in humans have focused on clinical or opportunistically collected samples, and none have yet investigated how social disadvantage influences the gene expression response to environmental challenges, such as pathogen infection, that may further amplify social environmental effects. The goal of the proposed research is to address these gaps by taking advantage of a unique population- representative sample of Detroit, collected by the Detroit Neighborhood Health Study (DNHS). The DNHS combines extensive neighborhood and individual-level data on social disadvantage with genotype data and, crucially, a biobank of cryopreserved peripheral blood mononuclear cells (PBMCs) from the same study subjects. I will use this resources to address three questions. First, what effect does social disadvantage, across multiple measures, have on baseline immune gene expression in humans? This aim will extend studies of social adversity and immune gene expression to an urban American population in which the relative impact of multiple types of social adversity (e.g., low socioeconomic status, recent trauma, neighborhood-level poverty) can be assessed. Second, to what degree does genotype moderate the effect of social environment on immune gene regulation? This analysis will highlight whether genetic differences are important in shaping susceptibility to social adversity, using immune gene expression as a model. Third, to what degree does social disadvantage affect the immune response to viral challenges (cytomegalovirus and Epstein-Barr virus) which have been shown to follow a social gradient in this population? This analysis will provide insight into whether social disadvantage-associated differences in immune function contribute to social gradients in viral infection by assessing the gene expression response to ex vivo viral challenge, in primary PBMCs collected from DNHS study subjects. These analyses will provide insight into the role of social adversity in shaping immune function across the spectrum of social disadvantage in the US. The proposed work will both add to the growing literature on social adversity and gene expression in humans, and shed light on the role of genotype and pathogen environment in creating heterogeneity in this relationship. It will also introduce two powerful methods from functional and statistical genomics (expression quantitative trait locus mapping and ex vivo challenges in cell culture) to the study of social gradients in health. By doing so, it will therefore not only represent a valuable training experience for the fellow, but will provide a broadly applicable model for biosocial studies of social adversity more generally.