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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.