Longitudinal Study of DNA Methylation and Epigenetic Clocks Prior to and Following Test-Confirmed COVID-19 and mRNA Vaccination

Abstract

The host epigenetic landscape rapidly changes during SARS-CoV-2 infection, and evidence suggest that severe COVID-19 is associated with durable scars to the epigenome. Specifically, aberrant DNA methylation changes in immune cells and alterations to epigenetic clocks in blood relate to severe COVID-19. However, a longitudinal assessment of DNA methylation states and epigenetic clocks in blood from healthy individuals prior to and following test-confirmed non-hospitalized COVID-19 has not been performed. Moreover, the impact of mRNA COVID-19 vaccines upon the host epigenome remains understudied. Here, we first examined DNA methylation states in the blood of 21 participants prior to and following test-confirmed COVID-19 diagnosis at a median time frame of 8.35 weeks; 756 CpGs were identified as differentially methylated following COVID-19 diagnosis in blood at an FDR adjusted p-value < 0.05. These CpGs were enriched in the gene body, and the northern and southern shelf regions of genes involved in metabolic pathways. Integrative analysis revealed overlap among genes identified in transcriptional SARS-CoV-2 infection datasets. Principal component-based epigenetic clock estimates of PhenoAge and GrimAge significantly increased in people over 50 following infection by an average of 2.1 and 0.84 years. In contrast, PCPhenoAge significantly decreased in people fewer than 50 following infection by an average of 2.06 years. This observed divergence in epigenetic clocks following COVID-19 was related to age and immune cell-type compositional changes in CD4+ T cells, B cells, granulocytes, plasmablasts, exhausted T cells, and naïve T cells. Complementary longitudinal epigenetic clock analyses of 36 participants prior to and following Pfizer and Moderna mRNA-based COVID-19 vaccination revealed that vaccination significantly reduced principal component-based Horvath epigenetic clock estimates in people over 50 by an average of 3.91 years for those who received Moderna. This reduction in epigenetic clock estimates was significantly related to chronological age and immune cell-type compositional changes in B cells and plasmablasts pre- and post-vaccination. These findings suggest the potential utility of epigenetic clocks as a biomarker of COVID-19 vaccine responses. Future research will need to unravel the significance and durability of short-term changes in epigenetic age related to COVID-19 exposure and mRNA vaccination.

Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell‐type deconvolution applied to human blood epigenetic clocks

“…Pang et al. ( 2022 ) demonstrated that COVID‐19 patients exhibit elevated PhenoAge and GrimAge, which they partially attributed to alterations in immune cell composition. Our study highlighted the confounding effect of immune cell composition on EAA in RA.…”

Risk Factors of Severe COVID-19: A Review of Host, Viral and Environmental Factors

“…Epigenetic markers of disease severity are concentrated near promoter regions (including the promoters of certain aging-related genes [ 48 ]) and include the hypermethylation of IFN-related and the hypomethylation of inflammatory genes [ 49 , 50 ]. In turn, COVID-19 might influence the markers included in biological age estimators and possibly, the process of aging as well [ 51 , 52 ].…”

Biological Age Predictors: The Status Quo and Future Trends

“…The impact of SARS-CoV-2 on epigenetic age has been another widely discussed topic. Pang A. et al [ 68 ] used a novel principal component version of epigenetic clocks in longitudinal studies [ 69 ] to measure the epigenetic aging in non-hospitalized pre- and post-COVID-19 patients and healthy controls. In the post-COVID-19 patients aged over 50, they observed an average 2.1-year increase in PCPhenoAge estimates and an average increase of 0.84 years in PCGrimAge estimates.…”