The incidence, prevalence, and burden of disease are unequally distributed within and across human populations. This heterogeneity is due in part to differences in exposure to social adversity, which is in turn patterned by variation in socioeconomic status, access to social support, and early life disadvantage. Indeed, experimental studies in animal models indicate that social adversity per se, even in the absence of differences in health care access or health risk behaviors, can increase disease susceptibility and shorten lifespan. They have also shown that social disadvantage both increases the expression of inflammation-related genes and alters the genome-wide immune response to bacterial and viral antigens. The goal of the proposed research is to investigate the translatability of these findings to human populations by studying the effects of social disadvantage on immune gene regulation in the context of health disparities. Specifically, the proposed study will characterize the relationship between socioeconomic status, past trauma, and peripheral blood mononuclear cell (PBMC) gene expression in samples collected by the Detroit Neighborhood Health Study (DNHS), a population-representative study of urban Detroit. The DNHS sample is ideal for this work because it is complemented by extensive information on individual and neighborhood-level socioeconomic disadvantage and, unusually for such studies, cryopreserved PBMCs for a representative subsample of study participants. Such samples are precisely the type used in studies of chronic social stress and immune gene regulation in nonhuman primates, thus maximizing comparability against findings from animal models. Notably, previous studies in rhesus macaques have shown that the effects of low social status on gene regulation are exaggerated after immune challenge. Such observations suggest that social disadvantage is particularly important in shaping the response to pathogens. However, while the effects of genotype, age, and sex on the genome-wide gene expression response to immune stimulation are well studied, little is known about the role of chronic social stress in humans. The proposed study will address this gap by investigating how social disadvantage patterns immune gene expression in cryopreserved PBMCs from the DNHS sample, both at baseline and following exposure to the bacterial endotoxin lipopolysaccharide. It will also investigate the relative contribution of social adversity and genetic ancestry in shaping the immune response. By comparing these data to data generated using a similar approach in nonhuman primate models, this approach will highlight the degree to which the causal effects of social adversity in animal models are mirrored in humans. It will therefore address key questions about the genomic mechanisms through which social disadvantage translates into health outcomes, with direct application to identifying the sources of health disparities during aging.
The social environment has a profound impact on human health and wellbeing during aging, and is likely one of the most important mediators of health disparities in the United States. This project takes advantage of samples from the Detroit Neighborhood Health Study to investigate whether social adversity predicts changes in gene regulation that could contribute to health disparities. By comparing these data to experimental results from nonhuman primates, its findings will contribute to understanding why disease incidence, prevalence, and burden differ across racial, ethnic, and socioeconomic lines.
