DNA methylation profiles at hospital admission are associated with subsequent severe COVID-19 outcomes

BACKGROUND: SARS-CoV-2 infection leads to a wide range of clinical manifestations ranging from asymptomatic to fatal cases. DNA methylation plays a crucial role in modulating host responses to viral infections; however, its potential for forecasting COVID-19 disease progression has not been fully explored. RESULTS: We aimed to explore the connection between DNA methylation and COVID-19 phenotypic trajectories by examining a subset of the IMPACC cohort (n = 75), which includes longitudinal samples from hospitalized COVID-19 patients grouped into five disease trajectory groups (TGs) based on respiratory severity during the acute phase of infection. Our findings reveal that DNA methylation is associated with respiratory status, hospitalization duration, and immune cell composition, including T cell depletion and band neutrophil accumulation during acute infection. DNA methylation profiles at hospital admission differ among TGs and are associated with subsequent disease progression. Furthermore, DNA de-methylation of specific distal enhancers correlated with TG, and DNA methylation patterns generally normalize post-resolution. Comparative analyses revealed that DNA methylation changes are more strongly associated with TGs than transcriptome profiles across time. CONCLUSIONS: This study highlights the association between DNA methylation and COVID-19 phenotypic trajectories and identifies CpG loci that could serve as potential biomarkers for identifying patients at heightened risk of severe COVID.