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.
The social environment is a key predictor of health and disease susceptibility during aging, and represents a major cause of health disparities in the United States. This project seeks to understand the biological mechanisms underlying these observations by quantifying the effect of social disadvantage on the regulation of the human immune system, including how these effects are moderated by genotype and viral infection. The results of this work will contribute to understanding how social gradients in health arise in urban American populations, which is important for predicting who is likely to be vulnerable, and under what conditions.
