{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:39:23Z","timestamp":1790991563464,"version":"4.1.0"},"reference-count":54,"publisher":"American Diabetes Association","issue":"4","license":[{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100018694","name":"HORIZON EUROPE Marie Sklodowska-Curie Actions","doi-asserted-by":"publisher","award":["721841 PainNET"],"award-info":[{"award-number":["721841 PainNET"]}],"id":[{"id":"10.13039\/100018694","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:p>The aim of this work was to describe the DNA methylation signature and identify genes associated with neuropathic pain in type 2 diabetes mellitus. We analyzed two independent cohorts: PROPGER, which comprised 72 patients with painful and 67 with painless diabetic neuropathy recruited at the German Diabetes Center in D\u00fcsseldorf, and PROPENG, which comprised 27 patients with painful and 65 with painless diabetic neuropathy recruited at the University of Manchester in the U.K. Genome-wide methylation data were generated using the Illumina Infinium MethylationEPIC v1.0 BeadChip. We used four different selection criteria to identify promising pain-related genes. Our findings revealed significant differences in methylation patterns between painful and painless diabetic neuropathy and identified a set of individual CpG sites of unique candidate genes associated with the painful phenotype. Several of these genes, including GCH1, MYT1L, and MED16, have been previously linked to pain-related phenotypes or diabetes. Through pathway enrichment analysis, we demonstrated that specific epigenetic signatures could contribute to the complex phenotype of diabetic neuropathy, and cluster analyses highlighted significant epigenetic dissimilarities between painful and painless phenotypes. Our results uncovered epigenetic differences between patients with painful and painless diabetic neuropathy and identified targeted genes linked to neuropathic pain through DNA methylation mechanisms. This approach holds promise for investigating other chronic pain conditions, such as secondary chronic pain from cancer treatment, thoracic surgery, and various transplant settings.<\/jats:p>\n               <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n                  <jats:p>Approximately one out of two patients with diabetes develops diabetic neuropathy; of these, 20% experience neuropathic pain. Risk factors for neuropathic pain are largely unknown; however, DNA methylation was recently associated with neuropathies and degeneration of nerve fibers. The aim of this work was to describe the DNA methylation signature and identify genes associated with neuropathic pain in type 2 diabetes mellitus (T2DM). We discovered distinct DNA methylation signatures that differentiate painful and painless neuropathy phenotypes associated with T2DM and identified genes with potential as therapeutic targets for neuropathic pain, such as GCH1, MYT1L, and MED16. This work can serve as reference hallmark for future studies on painful diabetic neuropathy and other chronic pain conditions.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db24-0930","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T18:30:01Z","timestamp":1736361001000},"page":"640-650","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":11,"title":["High-Resolution Whole-Genome DNA Methylation Revealed Unique Signatures of Painful Diabetic Neuropathy"],"prefix":"10.2337","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1536-5024","authenticated-orcid":false,"given":"Katarzyna Malgorzata","family":"Kwiatkowska","sequence":"first","affiliation":[{"name":"1Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Garagnani","sequence":"additional","affiliation":[{"name":"1Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy"},{"name":"2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Bonaf\u00e9","sequence":"additional","affiliation":[{"name":"1Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy"},{"name":"2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria G.","family":"Bacalini","sequence":"additional","affiliation":[{"name":"3Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Calzari","sequence":"additional","affiliation":[{"name":"5Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Ziegler","sequence":"additional","affiliation":[{"name":"6Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique M.","family":"Gerrits","sequence":"additional","affiliation":[{"name":"7Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharina G.","family":"Faber","sequence":"additional","affiliation":[{"name":"8Department of Neurology, Institute of Mental Health and Neuroscience, 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