The COVID-19 pandemic has affected African American populations disproportionately with respect to prevalence, morbidity, and mortality. Because gene expression profiles represent combined genetic, socioenvironmental, and physiological effects, and could provide therapeutic biomarkers and environmental mitigation strategies, we undertook a large-scale assessment of differential gene expression between African Americans and European Americans. To do this, we mined RNA-Seq datasets from normal and diseased (tumor) conditions whose metadata could be used to evaluate differential patterns. We observed widespread differential expression of genes implicated in COVID-19 and integral to epithelial boundary function, inflammation, infection, and reactive oxygen stress. Notably, expression of the little-studied F8A2 gene is up to 40-fold greater in African Americans. F8A2, like F8A1, encodes HAP40 protein, which mediates early endosome movement. African American gene expression signatures reveal increased number or activity of esophageal glandular cells and lung ACE2-positive basal keratinocytes. These findings have potential to establish prognostic signatures, refine approaches to minimizing risk of severe infection, and improve precision treatment of COVID-19.