African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors associated with immunologic functions and environmental exposures

Urminder Singh,Bruce J Aronow,Kyle M Hernandez,Eve Syrkin Wurtele

doi:10.1038/s41598-021-89224-1

Abstract

The COVID-19 pandemic has affected African American populations disproportionately with respect to prevalence, and mortality. Expression profiles represent snapshots of combined genetic, socio-environmental (including socioeconomic and environmental factors), and physiological effects on the molecular phenotype. As such, they have potential to improve biological understanding of differences among populations, and provide therapeutic biomarkers and environmental mitigation strategies. Here, we undertook a large-scale assessment of patterns of gene expression between African Americans and European Americans, mining RNA-Seq data from 25 non-diseased and diseased (tumor) tissue-types. We observed the widespread enrichment of pathways implicated in COVID-19 and integral to inflammation and reactive oxygen stress. Chemokine CCL3L3 expression is up-regulated in African Americans. GSTM1, encoding a glutathione S-transferase that metabolizes reactive oxygen species and xenobiotics, is upregulated. The little-studied F8A2 gene is up to 40-fold more highly expressed in African Americans; F8A2 encodes HAP40 protein, which mediates endosome movement, potentially altering the cellular response to SARS-CoV-2. African American expression signatures, superimposed on single cell-RNA reference data, reveal increased number or activity of esophageal glandular cells and lung ACE2-positive basal keratinocytes. Our findings establish basal prognostic signatures that can be used to refine approaches to minimize risk of severe infection and improve precision treatment of COVID-19 for African Americans. To enable dissection of causes of divergent molecular phenotypes, we advocate routine inclusion of metadata on genomic and socio-environmental factors for human RNA-sequencing studies.

Highlights

The COVID-19 pandemic has infected over 31 million people and killed over 970,000 worldwide as of September, 2020
Our analyses reveal consistent differences between European Americans and African Americans in pathways, genes, and cell types likely to impact the severity of COVID-19
In order to identify genes differentially-expressed (DE) between African American and European Americans, we constructed an aggregated dataset of 7142 RNA-Seq samples encompassing non-diseased tissues from GTEx and tumors from TCGA22,23

Summary

Introduction

The COVID-19 pandemic has infected over 31 million people and killed over 970,000 worldwide as of September, 2020 (https://coronavirus.jhu.edu/map.html). COVID-19 cases and deaths are disproportionately higher among African Americans in the US relative to European Americans[12,14] This disparity is caused in part by complex combinations of socio-economic factors, including underlying comorbidities, air quality, population density, and health care a ccess[12]; heritable factors in the human host influence COVID-19 symptoms[15,16,17,18,19]. In this study we seek to investigate potential differential expression of genes and pathways that may impact the severity of COVID-19 infection in African Americans. We seek to unravel the cellular origins of ancestry-associated differential gene expression through the use of Human Cell Atlas single-cell datasets from esophagus and lung tissues

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Discussion

Conclusion