ACE2 Expression and Clinical Biomarkers in COVID-19: Associations With Disease Severity

The COVID-19 pandemic, caused by SARS-CoV-2, has led to significant global mortality and morbidity. Angiotensin-converting Enzyme 2 (ACE2) has been identified as the primary receptor for viral entry into host cells and is believed to play a critical role in disease progression and severity. While ACE2 expression has been studied across various populations, data remains limited for underrepresented ethnic groups, such as the Kurdish population.

A prospective pilot study was conducted with 45 participants, divided equally into three groups (n = 15 each): mild cases, severe cases, and healthy controls. Whole blood samples were collected to assess hematological and biochemical parameters. ACE2 mRNA expression was analyzed using quantitative real-time PCR (qRT-PCR). Group comparisons were performed using one-way ANOVA for ΔCq values and nonparametric tests for nonnormally distributed variables.

ACE2 expression was significantly upregulated in patients with severe COVID-19, as indicated by lower ΔCq values compared to controls (mean difference = 0.568; adjusted p = 0.032). No significant difference was observed between mild cases and controls (p = 0.138). Furthermore, severe disease was characterized by markedly increased inflammatory markers (CRP, ESR, and ferritin) and hepatic enzymes (AST/GOT and ALP), alongside a decrease in lymphocyte counts. Also, CRP, ESR, and GPT were identified as the most significant predictors of disease severity in a machine learning analysis using XGBoost with SHAP interpretation. Demographic analysis revealed a significant age difference between controls and patients; however, no difference was observed between mild and severe cases. The sex distribution was comparable across all study groups.

Reduced lymphocyte counts and systemic inflammatory responses, specifically elevated CRP, ESR, and ferritin levels, were closely associated with disease severity in COVID-19. Although ACE2 expression results provide preliminary evidence that the Kurdish cohort's ACE2 mRNA expression is elevated in cases of severe COVID-19, its contribution to disease classification was minimal, indicating that multiple inflammatory and RAAS-related mechanisms, rather than ACE2 expression alone, drive disease progression.