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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.

SUBMITTER: Montesino-Goicolea S

PROVIDER: S-EPMC7711149 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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

Montesino-Goicolea Soamy S Sinha Puja P Huo Zhiguang Z Rani Asha A Foster Thomas C TC Cruz-Almeida Yenisel Y

Molecular pain 20200101

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 ...[more]

PMID: 33073674

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Project description:Our study aimed to identify differentially methylated regions (i.e., genomic region where multiple adjacent CpG sites show differential methylation) and their enriched genomic pathways associated with knee osteoarthritis pain (KOA). We recruited cognitively healthy middle to older aged (age 45-85) adults with (n = 182) and without (n = 31) self-reported KOA pain. We also extracted DNA from peripheral blood that was analyzed using MethylationEPIC arrays. The R package minfi (Aryee et al., 2014) was used to perform methylation data preprocessing and quality control. To investigate biological pathways impacted by differential methylation, we performed pathway enrichment analysis using Ingenuity Pathway Analysis (IPA) to identify canonical pathways and upstream regulators. Annotated genes within ± 5 kb of the putative differentially methylated regions (DMRs, p < 0.05) were subjected to the IPA analysis. There was no significant difference in age, sex, study site between no pain and pain group (p > 0.05). Non-Hispanic black individuals were overrepresented in the pain group (p = 0.003). At raw p < 0.05 cutoff, we identified a total of 19,710 CpG probes, including 13,951 hypermethylated CpG probes, for which DNA methylation level was higher in the groups with highest pain grades. We also identified 5,759 hypomethylated CpG probes for which DNA methylation level was lower in the pain groups with higher pain grades. IPA revealed that pain-related DMRs were enriched across multiple pathways and upstream regulators. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e., antigen presentation, PD-1, PD-L1 cancer immunotherapy, B cell development, IL-4 signaling, Th1 and Th2 activation pathway, and phagosome maturation). Moreover, in terms of upstream regulators, NDUFAF3 was the most significant (p = 8.6E-04) upstream regulator. Our findings support previous preliminary work suggesting the importance of epigenetic regulation of the immune system in knee pain and the need for future work to understand the epigenetic contributions to chronic pain.

Project description:We have reported child anxiety sensitivity (Child Anxiety Sensitivity Index [CASI]) predicts chronic postsurgical pain (CPSP). Herein, we evaluated DNA methylation profiles to understand the gene-environment interactions underlying CPSP and CASI, to identify shared, enriched, genomic pathways. In 73 prospectively recruited adolescents undergoing spine fusion, preoperative CASI and pain data over 12 months after surgery were collected. DNA from the peripheral blood of evaluable subjects with (n = 16) and without CPSP (n = 40) were analyzed using MethylationEPIC arrays. We identified 637 and 2,445 differentially DNA methylated positions (DMPs) associated with CPSP and CASI, respectively (P ≤ .05). Ingenuity pathway analysis of 39 genes with DMPs for both CPSP and CASI revealed enrichment of several canonical pathways, including GABA receptor (P = .00016 for CPSP; P =.0008 for CASI) and dopamine-DARPP32 feedback in cyclic adenosine monophosphate (P = .004 for CPSP and P =.00003 for CASI) signaling. Gene-gene interaction network enrichment analysis revealed participation of pathways in cell signaling, molecular transport, metabolism, and neurologic diseases (P < 10-8). Bioinformatic approaches to identify histone marks and transcription factor (TF) binding events underlying DMPs, showed their location in active regulatory regions in pain pathway relevant brain cells. Using Enrichr/Pinet enrichment and Library of Integrated Network-Based Cellular Signatures knockdown signatures, we identified TFs regulating genes with DMPs in association with CPSP and CASI. In conclusion, we identified epigenetically enriched pathways associated with CPSP and anxiety sensitivity in children undergoing surgery. Our findings support GABA hypofunction and the roles of the dopamine-DARPP32 pathway in emotion/reward and pain. This pilot study provides new epigenetic insights into the pathophysiology of CPSP and a basis for future studies in biomarker development and targetable interventions. PERSPECTIVE: Differential DNA methylation in regulatory genomic regions enriching shared neural pathways were associated with CPSP and CASI in adolescents undergoing spine surgery. Our findings support GABA hypofunction and the roles of the dopamine-DARPP32 pathway in emotion/reward contributing to behavioral maintenance of pain 10 to 12 months after surgery.

Project description:Compared to Non-Hispanic Whites (NHWs), individuals who self-identify as Non-Hispanic Blacks (NHBs) in the United States experience more severe and disabling chronic low back pain (cLBP). We hypothesized that differences in DNA methylation (DNAm) play a role in racial disparities in cLBP.PurposeTo determine the relationship between DNAm levels and racial group differences in adults with cLBP. Our study's secondary purpose was to perform a race-stratified comparison of adults with cLBP and pain-free controls and identify functional genomic pathways enriched by annotated differentially methylated genes.Patients and methodsWe recruited 49 NHBs and 49 NHWs (49 cLBP and 49 pain-free controls, PFCs), analyzed DNAm from whole blood using reduced representation bisulfite sequencing, and identified enriched genomic pathways.ResultsAmong participants with cLBP, we identified 2873 differentially methylated loci (DML; methylation differences of at least 10% and p < 0.0001), many of which were annotated to genes of importance to pain pathology. These DMLs significantly enriched pathways to involved in nociception/pain processing (Dopamine-DARPP32 Feedback in cAMP signaling, GABA Receptor Signaling, Opioid Signaling) and neuronal differentiation (e.g., Calcium Signaling, Axon Guidance Signaling, and Endocannabinoid Neuronal Synapse). Our race stratified analyses of individuals with cLBP versus PFCs revealed 2356 DMLs in NHBs and 772 DMLs in NHWs with p < 0.0001 and > 10% methylation difference. Ingenuity Pathway Analysis revealed that many pathways of significance to pain such as Corticotropin Releasing Hormone Signaling, White Adipose Tissue Browning, and GABA Receptor Signaling pathways, were more significant in NHBs than NHWs.ConclusionEven though an individual's self-identified race is a social construct, not a biological variable, racism associated with that classification affects virtually every aspect of life, including disease risk. DNAm induced alterations in stress signaling pathways may explain worse pain outcomes in NHBs.

Project description:ContextChronic pain is a major contributor to disability in older adults; however, the potential role of chronic pain as a risk factor for falls is poorly understood.ObjectiveTo determine whether chronic musculoskeletal pain is associated with an increased occurrence of falls in a cohort of community-living older adults.Design, setting, and participantsThe Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston Study is a population-based longitudinal study of falls involving 749 adults aged 70 years and older. Participants were enrolled from September 2005 through January 2008.Main outcome measureParticipants recorded falls on monthly calendar postcards mailed to the study center during an 18-month period.ResultsThere were 1029 falls reported during the follow-up. A report of 2 or more locations of musculoskeletal pain at baseline was associated with greater occurrence of falls. The age-adjusted rates of falls per person-year were 1.18 (95% confidence interval [CI], 1.13-1.23) for the 300 participants with 2 or more sites of joint pain, 0.90 (95% CI, 0.87-0.92) for the 181 participants with single-site pain, and 0.78 (95% CI, 0.74-0.81) for the 267 participants with no joint pain. Similarly, more severe or disabling pain at baseline was associated with higher fall rates (P < .05). The association persisted after adjusting for multiple confounders and fall risk factors. The greatest risk for falls was observed in persons who had 2 or more pain sites (adjusted rate ratio [RR], 1.53; 95% CI, 1.17-1.99), and those in the highest tertiles of pain severity (adjusted RR, 1.53; 95% CI, 1.12-2.08) and pain interference with activities (adjusted RR, 1.53; 95%CI, 1.15-2.05), compared with their peers with no pain or those in the lowest tertiles of pain scores.ConclusionsChronic pain measured according to number of locations, severity, or pain interference with daily activities was associated with greater risk of falls in older adults.

Dataset Information

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

Publications

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

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