DNA methylation profiles are associated with complex regional pain syndrome after traumatic injury.
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2019-10
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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.
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Bruehl, Stephen, Eric R Gamazon, Thomas Van de Ven, Thomas Buchheit, Colin G Walsh, Puneet Mishra, Krishnan Ramanujan, Andrew Shaw, et al. (2019). DNA methylation profiles are associated with complex regional pain syndrome after traumatic injury. Pain, 160(10). pp. 2328–2337. 10.1097/j.pain.0000000000001624 Retrieved from https://hdl.handle.net/10161/19639.
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Thomas John Van de Ven
Thomas Edward Buchheit
Dr. Buchheit serves as Director of the Regenerative Pain Therapies Program in the Duke Center for Translational Pain Medicine (CTPM), and practices Pain Medicine at both Duke University and the Durham VAMC. His research focus is on the local and systemic inflammatory mechanisms that drive pain in arthritis and nerve injury. He has led and participated in several multicenter research projects that have studied patients at Duke, the Durham VAMC, and Walter Reed National Military Medical Center, clarifying post-amputation pain phenotypes and mechanisms that drive the chronification of pain. These research pursuits have guided the clinical and translational programs of CTPM that strive develop biologically-based methods for the treatment of arthritis and degenerative musculoskeletal conditions. The program’s overarching goal is to move beyond opioids, steroids and anti-inflammatory medications for the treatment of pain.
Dr. Buchheit currently serves on the Editorial Board of Pain Medicine and recently completed service as Pain Medicine Division Chief in the Duke Department of Anesthesiology. He also serves on the Board of The Pain Society of the Carolinas and previously on the American Society of Anesthesiologists Pain Medicine Committee, (2012-2014), as an American Board of Anesthesiology Question Author (2011-2014), and President of Pain Society of the Carolinas (2015-2017).
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