Bruehl S, Gamazon ER, Van de Ven T, et al. - Researchers sought to determine the possible epigenetic mechanisms that may contribute to the development of complex regional pain syndrome (CRPS) after traumatic injury. Individuals developing CRPS (n = 9) and those developing non-CRPS neuropathic pain (n = 38) after undergoing amputation following military trauma were compared regarding DNA methylation profiles. Forty-eight differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites were identified between groups in Linear Models for Microarray (LIMMA) analyses, with the top gene COL11A1 meeting Bonferroni-adjusted P < 0.05. They observed the second largest differential methylation for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. The CRPS group was hypomethylated for all but 7 of the significant CpG sites. They observed significant enrichment of numerous functional Gene Ontology-Biological Process categories (false discovery rate-adjusted q value < 0.15), comprising multiple immune-related categories (eg, activation of immune response, immune system development, regulation of immune system processes, and antigen processing and presentation). In human protein-protein networks, differentially methylated genes were more highly connected than expected by chance; this supports the biological relevance of the findings. Validation of the results was done in an independent sample linking a DNA biobank with electronic health records (n = 126 CRPS phenotype, n = 19,768 non-CRPS chronic pain phenotype). Results thereby suggest the role of immune- and inflammatory-related factors in conferring the risk of developing CRPS after traumatic injury. In view of the validation findings, the potential of using electronic health records linked to DNA for genomic studies of CRPS was demonstrated.