Enrichment of genomic pathways based on differential DNA methylation profiles associated with chronic musculoskeletal pain in older adults: An exploratory study

Abstract

Our study aimed to identify differentially methylated CpGs/regions and their enriched genomic pathways associated with underlying chronic musculoskeletal pain in older individuals. We recruited cognitively healthy older adults with ( n = 20) and without ( n = 9) self-reported musculoskeletal pain and collected DNA from peripheral blood that was analyzed using MethylationEPIC arrays. We identified 31,739 hypermethylated CpG and 10,811 hypomethylated CpG probes ( ps ≤ 0.05). All CpG probes were clustered into 5966 regions, among which 600 regions were differentially methylated at p ≤ 0.05 level, including 294 hypermethylated regions and 306 hypomethylated regions (differentially methylated regions). Ingenuity pathway enrichment analysis revealed that the pain-related differentially methylated regions were enriched across multiple pathways. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e. antigen presentation, programed cell death 1 receptor/PD-1 ligand 1, interleukin-4, OX40 signaling, T cell exhaustion, and apoptosis) and gamma-aminobutyric acid receptor signaling. Further, Weighted Gene Correlation Network Analysis revealed a comethylation network module in the pain group that was not preserved in the control group, where the hub gene was the cyclic adenosine monophosphate-dependent transcription factor ATF-2. Our preliminary findings provide new epigenetic insights into the role of aberrant immune signaling in musculoskeletal pain in older adults while further supporting involvement of dysfunctional GABAergic signaling mechanisms in chronic pain. Our findings need to be urgently replicated in larger cohorts as they may serve as a basis for developing and targeting future interventions.

Whole-genome methylation profiling reveals regions associated with painful temporomandibular disorders and active recovery processes

“…Hypermethylation was observed in chronic painful TMD and subjects at V1 with acute painful TMD with pain persisting at 6 months after onset. This was in agreement with studies reporting increased methylation associated with chronic musculoskeletal pain in adults 44 and postsurgical pain in children. 10 However, these findings are contrasted by hypomethylation at V2 in those with pain persisting at 6 months.…”

“…Differential methylation at this locus has been associated with prenatal chemical exposure 61 and early life experience of famine, 35 as well as with PTSD. 52 To date, several reports describe an association between the RNF39 locus and chronic pain, either because of hypomethylation with musculoskeletal pain 44 or conversely, because of hypermethylation with chronic widespread pain following motor vehicle collision 6 and migraine. 21 We also observed hypomethylation in chronic painful TMD and in those individuals with acute TMD with persistent pain at 6 months after onset at V1 for a DMR spanning the promoter and first exon of the zinc finger 718 (ZNF718) gene.…”

“…Differential methylation at this locus has been associated with prenatal chemical exposure 61 and early life experience of famine, 35 as well as with PTSD. 52 To date, several reports describe an association between the RNF39 locus and chronic pain, either because of hypomethylation with musculoskeletal pain 44 or conversely, because of hypermethylation with chronic widespread pain following motor vehicle collision 6 and migraine. 21…”

Vitamin D Metabolism Genes Are Differentially Methylated in Individuals with Chronic Knee Pain

“…To perform between-array normalization and regress out variability explained by the control probes, functional normalization was employed. Details on all CpG probes have been previously reported by our group [14].…”