Deoxyribonucleic Acid Methylation of Circadian Clock Genes in Persons with High Impact Pain

Based on the bidirectional associations between chronic pain and sleep disorders, investigating circadian physiology in persons with chronic pain is needed. A potential contributor linking sleep disturbances in chronic pain conditions includes epigenetic alterations in genes regulating circadian clocks in persons with and without chronic pain. The purpose of this study is to examine DNA methylation differences of core circadian clock genes by chronic pain status. We hypothesize individuals with high impact chronic pain have significant DNA methylation differences in genes known to be important for circadian physiology compared to pain-free controls. Participants (n=106) aged 45-85 years, with varying degrees of chronic knee pain completed self-reported measures to determine pain impact (ie., graded chronic pain scale), along a blood draw for DNA extraction and epigenetic analysis (ie., MethylationEPIC arrays). R was used to perform methylation data preprocessing and quality control (minfi package) and differential methylation analyses focusing on the core circadian genes (PER1, PER2, PER3, DBP, CLOCK, CRY1, CRY2, ARNTL, NR1D1, and NR1D2). Individuals with high impact chronic pain had 15 differentially methylated probes (DMPs) at p<0.05, and 2 DMPs at p<0.01 compared to no pain controls. Specifically, individuals with high impact chronic pain had significant hypomethylation in a probe located at an exon of the PER3 gene and hypermethylation in a probe within an intron of the NKIRAS1 and NR1D2 genes. Future studies are needed to determine whether epigenetic alterations of these identified regions could serve to develop novel therapeutic targets. Funding: This work was supported by NIH/NIA Grants R01AG067757 (YCA); and R37AG033906 (RBF).