DNA methylation profiles are associated with complex regional pain syndrome after traumatic injury

Abstract

Factors contributing to development of complex regional pain syndrome (CRPS) are not fully understood. This study examined possible epigenetic mechanisms that may contribute to CRPS after traumatic injury. DNA methylation profiles were compared between individuals developing CRPS (n = 9) and those developing non-CRPS neuropathic pain (n = 38) after undergoing amputation following military trauma. Linear Models for Microarray (LIMMA) analyses revealed 48 differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites between groups (unadjusted P's < 0.005), with the top gene COL11A1 meeting Bonferroni-adjusted P < 0.05. The second largest differential methylation was observed for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. For all but 7 of the significant CpG sites, the CRPS group was hypomethylated. Numerous functional Gene Ontology-Biological Process categories were significantly enriched (false discovery rate-adjusted q value <0.15), including multiple immune-related categories (eg, activation of immune response, immune system development, regulation of immune system processes, and antigen processing and presentation). Differentially methylated genes were more highly connected in human protein–protein networks than expected by chance (P < 0.05), supporting the biological relevance of the findings. Results were validated in an independent sample linking a DNA biobank with electronic health records (n = 126 CRPS phenotype, n = 19,768 non-CRPS chronic pain phenotype). Analyses using PrediXcan methodology indicated differences in the genetically determined component of gene expression in 7 of 48 genes identified in methylation analyses (P's < 0.02). Results suggest that immune- and inflammatory-related factors might confer risk of developing CRPS after traumatic injury. Validation findings demonstrate the potential of using electronic health records linked to DNA for genomic studies of CRPS.

Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review

“…The greatest methylation differences were identified in genes that belong to the human leukocyte antigen (HLA) system, with 3 of the most differentially methylated CpGs belonging to HLA-DBR6 , HLA-DBR1 and HLA-DQA1 , all found to be hypermethylated in MUHO. HLA-DRB6 is associated with immunological and neurological disorders such as multiple sclerosis ( 76 ), Alzheimer’s disease ( 77 ) or chronic pain ( 78 ). Nevertheless, given that the HLA system regulates the adaptive immune response, it can be hypothesized that this gene may play a role in mediating the AT inflammatory state in MUHO.…”

DNA Methylation May be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1

“…It has been observed that persistent pain can alter expression of DNMTs. It is reported that treatment that promoted DNA demethylation might have resulted in mechanical and thermal antinociception in a mouse oral cancer model [24]. Furthermore, DNA methylation regulates several additional pain and analgesiarelated genes in various pain models [25].…”

Genome-Wide Epigenomic Analyses in Patients With Nociceptive and Neuropathic Chronic Pain Subtypes Reveals Alterations in Methylation of Genes Involved in the Neuro-Musculoskeletal System

“…Twenty healthy volunteers matched for sex, age, and BMI who reported no pain and taking no medication were recruited as the control group. An approximate number of patients was estimated from a previous study on DNA methylation profile in pain patients 7 . In order to minimize potential sources of bias, patients were matched on the basis of their age, sex, BMI, time since injury, location of the lesion, pain medication, pain levels, anxiety and depression levels.…”

“…Epigenetic factors might be involved in the transition from acute to chronic pain and chronic pain maintenance 7 . A few studies have confirmed the epigenetic control of the two main types of chronic pain, NOCI and NEURO, in humans.…”