Host methylation predicts SARS-CoV-2 infection and clinical outcome

Abstract

Background Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR1. Host epigenome manipulation post coronavirus infection2–4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. Methods We customized Illumina’s Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. Results Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g.IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. Conclusions In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections.

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study

“…We observed that the EPIMISC signature was present only in 7.8% (5 out 64) of patients with other viral respiratory infections (GSE167202; Ref. 29 ). The interrogated GSE167202 cohort included rhinovirus/enterovirus (33%), influenza A (17%), metapneumovirus (13%), influenza B (11%), other coronavirus (11%), respiratory syncytial virus (9%), parainfluenza (5%), and adenovirus (2%) cases.…”

Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion

“…These early epigenetic changes occur prior to transcriptional manifestations and in this cohort were also more stable and predictive of disease severity than gene expression alone. These ndings suggest that epigenetic approaches focusing on chromatin accessibility may offer even greater promise than other host-based molecular diagnostics and predictive tools, as has been suggested for DNA methylation-based pro les 25 . Our work is consistent with previous studies that identi ed DNA-methylation signatures, which included viral response and interferon signaling, that will predict SARS-CoV-2 infection and clinical outcome 25 and with genome-wide DNA methylation signatures associated with severe COVID-19 that highlight hypermethylation in IFN-related genes, hypomethylation in in ammatory genes and increased epigenetic age 26 .…”

“…These ndings suggest that epigenetic approaches focusing on chromatin accessibility may offer even greater promise than other host-based molecular diagnostics and predictive tools, as has been suggested for DNA methylation-based pro les 25 . Our work is consistent with previous studies that identi ed DNA-methylation signatures, which included viral response and interferon signaling, that will predict SARS-CoV-2 infection and clinical outcome 25 and with genome-wide DNA methylation signatures associated with severe COVID-19 that highlight hypermethylation in IFN-related genes, hypomethylation in in ammatory genes and increased epigenetic age 26 . Interestingly, CD14+ monocytes underwent the most extensive chromatin remodeling over time and exhibited epigenetic pro les at early seronegative times that distinguish disease severity.…”

Epigenetics at the Intersection of COVID-19 Risk and Environmental Chemical Exposures

“…In a 2021 genome-wide association meta-analysis consisting of nearly 50,000 participants from across the globe, 13 loci were identified as being associated with SARS-CoV-2 infection, critical illness, or hospitalization due to COVID-19 [ 31 ]. By contrast, two recent epigenome-wide association studies (EWASs) revealed methylation levels at over 13,000 5’-C-phosphate-G-3’ (CpG) sites that were associated with infection status and 44 CpG sites that were associated with hospitalization requiring respiratory support [ 32 ••, 33 ••, 34 ], suggesting that epigenetic mechanisms also contribute to the immune responses to SARS-CoV-2. Epigenetic mechanisms modify gene expression without changing the underlying DNA sequence [ 34 ] and, in addition to DNA methylation at CpG sites, include modifications to histones (proteins in the cell nucleus that DNA is wrapped around) and non-coding microRNA (miRNA) [ 34 ].…”