Blood DNA Methylation in Post-Acute Sequelae of COVID-19 (PASC): a Prospective Cohort Study

Background: DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified. Methods: In this single center prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing (WGS). PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity. Findings: 103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harboring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life.]]>
Inclusion CriteriaPatients were eligible for enrollment if they were older than 18 years, had previously tested positive for COVID-19, and reported lingering symptoms after disease recovery. Informed consent was obtained from the patient directly for every patient in this study.Exclusion Criteria presence of a known comorbidity with symptoms that could be attributable to PASC, including chronic pulmonary diseases, depression, fibromyalgia, and otherscancerrecent infection other than COVID-19current or recent pregnancyintake of immunosuppressive medications including mycophenolate, corticosteroids, and othersinability to provide consent]]>
Although significant progress has been made on the understanding of COVID-19 pathophysiology and treatment options, millions of surviving patients still develop post-acute sequelae of COVID-19 (PASC). PASC involves many chronic deficits that undermine individuals' quality of life, reinsertion to work, and other relevant outcomes. Given the diversity of PASC-associated deficits, this entity has been extraordinarily difficult to characterize accurately. Indeed, biomarkers of PASC are nonspecific or relevant to single-organ dysfunctions. There are currently no global PASC biomarkers encompassing multi-organ deficits. The identification of global PASC molecular signatures could facilitate diagnosis and severity scoring; and provide important insights into the process pathophysiology.]]>