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

Soamy Montesino-Goicolea,Thomas C Foster,Asha Rani,Puja Sinha,Zhiguang Huo,Yenisel Cruz-Almeida

doi:10.1177/1744806920966902

Soamy Montesino-Goicolea, Thomas C Foster + Show 4 more

Open Access

https://doi.org/10.1177/1744806920966902

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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.

Highlights

Chronic pain prevalence increases with age leading to significant distress and disability.[1,2,3,4,5] In particular, current interventions do not provide sufficient levels of pain relief in older individuals with musculoskeletal pain.[6,7] Further, available pain treatments such as nonsteroidal anti-inflammatories are often accompanied by detrimental side effects that limit their long-term use in this vulnerable population
We evaluated DNA methylation profile associations with self-reported musculoskeletal pain in community-dwelling older adults and employed an integrative computational analysis to identify common, targetable pathways enriched by the genes with differentially methylated CpG sites
We focus our discussion on the top 10 enriched pathways identified, which were reflective of cellular responses important for immune signaling and gamma-aminobutyric acid (GABA) receptor signaling

Summary

Introduction

Chronic pain prevalence increases with age leading to significant distress and disability.[1,2,3,4,5] In particular, current interventions do not provide sufficient levels of pain relief in older individuals with musculoskeletal pain.[6,7] Further, available pain treatments such as nonsteroidal anti-inflammatories are often accompanied by detrimental side effects that limit their long-term use in this vulnerable population. There is an increasing understanding of potential neurobiological mechanisms underlying musculoskeletal pain, mechanistic human studies are currently lacking, which may help identify potential therapeutic targets in the older population.

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