Perfis proteômico e genômico associados à severidade da COVID-19 em uma coorte de pacientes do Rio de Janeiro

Abstract

COVID-19 is an infectious disease caused by SARS-CoV-2 and was characterized as one of the major global public health emergencies between March 2020 and May 2023. Although most infected individuals develop mild to moderate respiratory symptoms, a subset progresses to severe disease, often associated with inflammatory and thrombotic dysfunctions and adverse clinical outcomes. Even after the expansion of vaccination coverage and the reduction in severe cases, SARS-CoV-2 still accounts for a significant proportion of viral Acute Respiratory Distress Syndrome (ARDS) cases in Brazil. In this context, the present study aimed to investigate proteomic and genomic signatures associated with COVID-19 severity, seeking to identify biomarkers and molecular pathways potentially involved in the disease pathophysiology. The study included patients aged ≥18 years with COVID-19 confirmed by RT-PCR, recruited from HNMD and NEEDIER-UFRJ. An integrative approach was employed using different molecular biology techniques, including oxidative stress assessment, proteomics, and genomic association analysis, taking into account the patients’ clinical status and outcomes. The results demonstrated a significant increase in lipid peroxidation in patients with elevated D-dimer levels and in those who required mechanical ventilation, indicating higher oxidative stress in these groups. Proteomic analysis, performed on pooled samples stratified by D-dimer levels (≥2000 μg/L and <2000 μg/L), identified 12 differentially expressed proteins, highlighting the upregulation of proteins associated with coagulation (ATRN, ITIH4, APOB, C5, SERPINA1, PPBP, and PROS1) and the downregulation of proteins related to the immune response (C4A, IGHG1, IGHG3, MYH9, and B2M). Functional enrichment analyses supported these findings, showing that downregulated biological processes and signaling pathways were mainly associated with immune response, whereas upregulated processes and pathways were primarily involved in inflammation, coagulation, and chemotaxis— a pattern consistent with the thromboinflammation described in severe COVID-19. Complementarily, genomic association analysis comparing patients with severe (cases) and mild (controls) disease identified polymorphisms in the EML1 gene (rs11628837, rs8020741, and rs4900448) associated with a protective effect (OR = 0.3648; 95% CI: 0.2418–0.5503; p = 1.528 × 10⁻⁶). Overall, these results allowed the characterization of a molecular profile associated with severe COVID-19, confirmed the role of D-dimer as a robust prognostic marker, and suggested novel molecular biomarkers and biological pathways with potential for therapeutic intervention.