Background: Viral infections, including COVID-19, are associated with an increased risk for type 1 diabetes (T1D), but potential underlying mechanisms remain unexplored. We evaluated whether COVID-19 or influenza A infection is characterized by differential DNA methylation at immune and T1D susceptibility genes in young children at risk for T1D.
Methods: Epigenome-wide association analysis using the Illumina MethylationEPIC microarray was performed in blood taken at age 1.5 years (IQR, 1.49-1.52 y) from 740 prospectively followed children with increased risk of T1D. SARS-CoV-2 and influenza A H1N1 antibodies were monitored at 2-4-month intervals from age 6 months to identify infection.
Results: COVID-19 and influenza infection occurred prior to the DNA methylation sample in 81 and 74 children, respectively. Of these, infection occurred within 3 months of the DNA methylation sample (recent infection) in 43 and 22 children. Compared to children without COVID-19 or influenza A infection, children with recent COVID-19 infection showed differential methylation at key immune- and antiviral genes, including ADAR, IFI44L, MX1 and OASL. In addition to ADAR, six further T1D susceptibility genes, including the SARS-CoV-2 cell entry receptor neuropilin-1, had differential methylation at nearby CpGs in children infected by SARS-CoV-2. A quantitatively less differential methylation was also observed in children with an earlier COVID-19 infection at some of these CpG sites. Infections with influenza showed no associations.
Conclusion: Children with SARS-CoV-2 infection showed sustained DNA methylation changes at genes critical for antiviral response and T1D susceptibility, potentially contributing to immune dysregulation and promotion of the autoimmune process underlying T1D.
Keywords: Autoimmunity; COVID-19; DNA methylation; Influenza; SARS-CoV-2; Type 1 diabetes; Viral infection.
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