COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

Abstract

Rationale: Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 (angiotensin-converting enzyme 2), and TMPRSS2 (transmembrane protease serine 2) mediate viral infection of host cells. We reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells among patients with asthma may identify subgroups at risk for COVID-19 morbidity.Objectives: To determine the relationship between demographic features and sputum ACE2 and TMPRSS2 gene expression in asthma.Methods: We analyzed gene expression for ACE2 and TMPRSS2, and for ICAM-1 (intercellular adhesion molecule 1) (rhinovirus receptor as a comparator) in sputum cells from 330 participants in SARP-3 (Severe Asthma Research Program-3) and 79 healthy control subjects.Measurements and Main Results: Gene expression of ACE2 was lower than TMPRSS2, and expression levels of both genes were similar in asthma and health. Among patients with asthma, male sex, African American race, and history of diabetes mellitus were associated with higher expression of ACE2 and TMPRSS2. Use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2, but treatment with triamcinolone acetonide did not decrease expression of either gene. These findings differed from those for ICAM-1, where gene expression was increased in asthma and less consistent differences were observed related to sex, race, and use of ICS.Conclusions: Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID-19 morbidity.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; asthma.

Figure 1.

Sputum gene expression at the initial study visit in participants with asthma (n = 330) and healthy participants (n = 79). (A and B) No difference in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related genes, ACE2 (angiotensin-converting enzyme 2), and TMPRSS2 (transmembrane protease serine 2), between participants with asthma and healthy participants. (C) Gene expression for the rhinovirus-binding protein ICAM-1 (intercellular adhesion molecule 1) was higher in participants with asthma than in healthy participants.

Figure 2.

Sputum gene expression of ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane protease serine 2) is strongly correlated in both (A) healthy participants and (B) participants with asthma. Best fit line was fitted using a cubic smoothing spline.

Figure 3.

Multivariate mixed-effects models displaying the effect of demographic features and comorbidities on sputum gene expression. The multivariate models include each demographic or comorbidity feature and are also controlled for the three asthma control factors (FEV₁% predicted, number of asthma exacerbations in the past year, and asthma symptoms as measured by the score on the Asthma Control Test). The figure shows estimates for the mean effect (regression coefficient) of each demographic or comorbidity feature on sputum gene expression expressed on a log₁₀ change. The effect size displayed is per 10-year change for age and per 10-unit change for body mass index (BMI). *The reference group for race is white. Two subjects with American Indian and Alaska Native race were not included in the race analysis. Data are presented as mean difference (circles) and 95% confidence interval (whiskers). ACE2 = angiotensin-converting enzyme 2; ICAM-1 = intercellular adhesion molecule 1; TMPRSS2 = transmembrane protease serine 2.

Figure 4.

(A) Multivariate mixed effects models displaying the effect of inhaled corticosteroid use on sputum gene expression. Models incorporate the same demographic features in Figure 3 and the three asthma control factors. ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane protease serine 2) are statistically significantly lower in patients on inhaled corticosteroids than in the control group of subjects not on inhaled corticosteroids. Data are presented as mean effect (circles) and 95% confidence interval (whiskers). (B) No change in sputum gene expression in subjects with asthma (n = 158) before (baseline) and 2 weeks after a 40-mg injection of triamcinolone (post-CS). Comparison of means was performed using a matched paired t test. ICAM-1 = intercellular adhesion molecule 1. CS = coritcosteroid.