Racial/Ethnic Variation in Nasal Gene Expression of Transmembrane Serine Protease 2 (TMPRSS2)

Coronavirus disease 2019 (COVID-19) has disproportionately affected communities of color.^1,2 In many areas of the US, infection and death rates for COVID-19 are 2 to 3 times higher in Black individuals than their proportion of the population.^1,2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spread by airway contact and uses transmembrane serine protease 2 (TMPRSS2) to facilitate viral entry and spread.³ Host-expressed TMPRSS2 on nasal and bronchial epithelium activates the SARS-CoV-2 spike protein and cleaves the angiotensin-converting enzyme 2 receptor to which the virus binds, enabling SARS-CoV-2 to enter the body.³

Racial/ethnic differences in TMPRSS2 gene–related activity in prostate tissue have been associated with disproportionately higher incidence of prostate cancer in Black men vs White men.⁴ Recognizing that many factors contribute to COVID-19 health disparities, we investigated TMPRSS2 nasal gene expression in a racially/ethnically diverse cohort.

This cross-sectional study used nasal epithelium collected during 2015-2018 from individuals within the Mount Sinai Health System (New York, New York), a cohort we have previously studied.⁵ Healthy individuals and individuals with asthma aged 4 to 60 years underwent nasal brushing for research on asthma biomarkers.

Self-identified race/ethnicity was queried given prior associations between race/ethnicity and asthma. RNA isolation of brushings followed by RNA sequencing, sequence alignment, and normalization were performed. The Mount Sinai institutional review board approved the study. Written informed consent was obtained from participants.

Linear regression modeling adjusted for age, sex, and asthma with TMPRSS2 expression in log₂ counts per million as the dependent variable and self-identified race/ethnicity as the independent variable was performed using R version 3.6.0 (R Foundation for Statistical Computing). Two-sided tests and a significance threshold of P ≤ .05 were used.

The cohort (n = 305) was 8.2% Asian individuals, 15.4% Black individuals, 26.6% Latino individuals, 9.5% individuals of mixed race/ethnicity, and 40.3% White individuals. Of the participants, 48.9% were male and 49.8% had asthma.

Among the racial/ethnic groups, nasal gene expression of TMPRSS2 was highest in Black individuals (n = 47; mean, 8.64 [95% CI, 8.41-8.86] log₂ counts per million) compared with Asian individuals (n = 25; mean, 8.07 [95% CI, 7.74-8.40] log₂ counts per million), Latino individuals (n = 81; mean, 8.02 [95% CI, 7.90-8.14] log₂ counts per million), individuals of mixed race/ethnicity (n = 29; mean, 7.97 [95% CI, 7.77-8.16] log₂ counts per million), and White individuals (n = 123; mean, 8.04 [95% CI, 7.94-8.15] log₂ counts per million) (Figure).

TMPRSS2 expression was significantly higher in Black individuals compared with Asian, Latino, mixed race/ethnicity, and White individuals (all P < .001) based on linear regression (Figure and Table). There were no significant associations between TMPRSS2 expression and sex, age, or asthma.

This study of nasal epithelial gene expression in a racially/ethnically diverse cohort showed significantly higher expression of TMPRSS2 in Black individuals compared with other self-identified races/ethnicities. Given the essential role of TMPRSS2 in SARS-CoV-2 entry,³ higher nasal expression of TMPRSS2 may contribute to the higher burden of COVID-19 among Black individuals. TMPRSS2 inhibitors such as camostat mesylate³ are undergoing clinical trials to test their utility for COVID-19 treatment. The finding of racial/ethnic variation in TMPRSS2 expression emphasizes that inclusion of diverse participants and analyses stratified by race/ethnicity should be incorporated into such trials.

The limitations of this study include its modest cohort size, constraint to 1 metropolitan region, and participant age range of 4 to 60 years. Although this study suggests one factor that may partially contribute to COVID-19 risk among New York–area Black individuals, many additional factors are likely, especially because gene expression and race/ethnicity reflect multiple social, environmental, and geographic factors.

Corresponding Author: Supinda Bunyavanich, MD, MPH, MPhil, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 (supinda@post.harvard.edu).

Accepted for Publication: August 24, 2020.

Published Online: September 10, 2020. doi:10.1001/jama.2020.17386

Author Contributions: Dr Bunyavanich had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bunyavanich.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Bunyavanich.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bunyavanich.

Obtained funding: Bunyavanich.

Administrative, technical, or material support: Bunyavanich.

Supervision: Bunyavanich, Vicencio.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by grant R01 AI118833 from the National Institutes of Health.

Role of the Funder/Sponsor: The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Robert Griffin, MD, PhD (Hospital for Special Surgery), and Anh Do, PhD, and Yoojin Chun, MS (both with the Icahn School of Medicine at Mount Sinai), for their assistance with manuscript preparation. None received compensation for their contributions.