Background & Aims

Chronic stress is strongly associated with chronic pain, often co-existing and contributing to one another in a bidirectional manner (1). Emerging evidence implicates epigenetic alterations in the development and progression of chronic pain conditions (2-4). As such, epigenetic modifications, such as DNA methylation (DNAm), may help explain the complex interaction between stress and chronic pain (5-7), although few studies to date have explored these relationships. The present exploratory study aimed to compare DNAm patterns across known stress-related genes in middle- and older-aged adults with and without high-impact chronic knee pain. Based on previous work, we hypothesized differential DNA methylation across stress-related genes in persons with high-impact chronic knee pain compared to pain-free controls.

Methods

Cross-sectional analysis of 106 community-dwelling adults aged 45-85 years who reported no pain (n=31, 14.6%) or high-impact knee pain (n=75, 35.2%), and completed information regarding demographic, pain impact (i.e., Graded Chronic Pain Scale to classify pain-impact grades) (8) and stress (Perceived Stress Scale) (9,10) as well as a venipuncture procedure. DNA was extracted and analyzed using Infinium MethylationEPIC arrays (>850k CpGs). We explored differentially methylated probes (DMPs) and differentially methylated genomic regions (DMRs), as well as functional annotation by genomic features across the 30 genes. All analyses were performed in R.

Results

Participants had a mean age of 57.8 years, 60.6% were female, and identified as non-Hispanic White (53.1%) or Black/African American (46.9%). Perceived stress was elevated in high-impact pain compared to no pain (16.6±6.3 vs 11.5±6.3, p<0.001) We identified 20 DMPs in individuals with high-impact pain relative to those with no pain, including 6 hypermethylated and 14 hypomethylated CpG probes (p<0.05), which corresponded to the following genes: BDNF, GAD1, CRHR1, FKBP5, TXNRD2, IL6, ACE, OPRM1, NPY, TH, POU3F1, CCL13/CCL1, DNMT1, and MEG3. Only one DMR, corresponding to ACE, was identified as hypomethylated in high-impact pain compared to no pain. Compared to the null distribution of CpG probes included in the Illumina EPIC array, hypermethylated probes tended to be enriched in intron regions (32.2% vs 66.7%, respectively), whereas hypomethylated probes tended to be enriched in promoter regions (47.0% vs 64.3%, respectively); however, these findings were not statistically significant.

Conclusions

This exploratory study identified several differentially methylated CpG probes in individuals with high-impact pain across stress-related genes. These findings point to the role of epigenetic modifications in the pathophysiology of chronic pain in knee OA and its relationship with chronic stress. Studies with larger samples and longitudinal designs are needed to fully elucidate the influence of epigenetic modifications on stress and chronic pain conditions.

References

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Presenting Author

Javier Tamargo

Poster Authors

Javier Tamargo

PhD

University of Florida

Lead Author

Larissa Strath

PhD

University of Florida

Lead Author

Ariana Robinson

University of Florida

Lead Author

Yutao Zhang

MS

University of Florida

Lead Author

Zhiguang Huo

PhD

University of Florida

Lead Author

Yenisel Cruz-Almeida

University of Florida

Lead Author

Topics

  • Mechanisms: Biological-Molecular and Cell Biology