Social disadvantage and immune gene expression in an urban US population

项目摘要 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， 健康风险行为或健康选择不能完全解释这种关系， 基因调节也发挥着作用。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，迄今为止，大多数人类研究 已经专注于临床或机会主义收集的样本，还没有人调查社会如何 不利影响基因表达对环境挑战的反应，例如病原体感染， 这可能会进一步扩大社会环境影响。 拟议研究的目标是通过利用独特的人群来解决这些差距- 底特律的代表性样本，由底特律邻里健康研究（DNHS）收集。DNHS 结合了广泛的社区和个人层面的社会劣势数据与基因型数据， 重要的是，来自相同研究受试者的冷冻保存的外周血单核细胞（PBMC）的生物库。 我将利用这些资源回答三个问题。首先，社会劣势在多个方面 在人类的免疫基因表达基线上有多少？这一目标将扩展对社会逆境的研究 和免疫基因表达对美国城市人口的影响，其中多种类型的免疫系统的相对影响， 社会逆境（例如，社会经济地位低、最近的创伤、社区一级的贫困）。 第二，基因型在多大程度上调节了社会环境对免疫基因调节的影响？ 这项分析将突出遗传差异是否在塑造对社会逆境的易感性方面很重要， 使用免疫基因表达作为模型。第三，社会劣势在多大程度上影响免疫力 对病毒挑战（巨细胞病毒和EB病毒）的反应，这些病毒挑战已被证明遵循社会 在这一人群中，？这项分析将提供洞察力，是否社会disorder相关 通过评估基因表达，免疫功能的差异有助于病毒感染的社会梯度 在从DNHS研究受试者收集的原代PBMC中，对离体病毒攻击的反应。 这些分析将提供对社会逆境在塑造免疫功能中的作用的见解， 美国社会的弱势群体。这项拟议中的工作既将增加关于社会问题的越来越多的文献， 逆境和基因表达，并阐明基因型和病原体环境在人类中的作用， 在这种关系中产生异质性。它还将介绍两个功能强大的方法， 统计基因组学（表达数量性状基因座作图和细胞培养中的离体挑战） 研究健康的社会梯度。因此，这样做不仅是一种宝贵的培训经验， 为研究员，但将提供一个广泛适用的模式，生物社会研究的社会逆境更普遍。

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.