{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:31:48Z","timestamp":1785843108410,"version":"3.56.0"},"reference-count":44,"publisher":"Korean Diabetes Association","issue":"1","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["PH-112-GP-04"],"award-info":[{"award-number":["PH-112-GP-04"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["PH-112-PP-10"],"award-info":[{"award-number":["PH-112-PP-10"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Science and Technology Council in Taiwan","award":["MOST 114-2221-E-400-003-MY3"],"award-info":[{"award-number":["MOST 114-2221-E-400-003-MY3"]}]}],"content-domain":{"domain":["e-dmj.org"],"crossmark-restriction":true},"short-container-title":["Diabetes Metab J"],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:p>Background: Type 2 diabetes mellitus (T2DM) is a complex, multifactorial disease with a significant global burden. Although genome-wide association studies (GWAS) have identified many T2DM-associated variants, most lie in non-coding regions, making it difficult to interpret their functional roles.Methods: We aimed to identify genetically regulated Cytosine\u2013phosphate\u2013Guanine (CpG) sites associated with T2DM by conducting a methylome-wide association study (MWAS), followed by Mendelian randomization (MR) and functional validation using human pancreatic cells and mouse models. MWAS was performed using summary statistics from large-scale GWAS and a DNA methylation (DNAm) prediction model to test associations between genetically predicted DNAm and T2DM.Results: We identified 111 CpG sites significantly associated with T2DM in Europeans, including 8 novel sites near genes not previously linked to T2DM. These findings were replicated in independent datasets. Many CpGs also showed associations with cardiometabolic traits, highlighting shared epigenetic mechanisms. Trans-ethnic MR analysis confirmed consistent effects for six CpGs in East Asians. Functional analysis revealed that several CpGs regulate gene expression in human pancreatic \u03b1- and \u03b2-cells. Among them, 2\u00b4-5\u00b4-oligoadenylate synthetase like (OASL) expression, regulated by a significant CpG, was differentially expressed in \u03b1-cells of T2DM cases compared to controls. Supporting evidence from mouse models suggests a role for OASL in glucose regulation.Conclusion: Our study identifies novel genetically regulated CpG sites associated with T2DM risk and highlights OASL as a potential epigenetic regulator of glucose metabolism in \u03b1-cells. These findings provide mechanistic insights into the epigenetic architecture of T2DM and suggest potential targets for cross-ethnic biomarker development and therapeutic intervention.<\/jats:p>","DOI":"10.4093\/dmj.2025.0041","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T08:08:16Z","timestamp":1761638896000},"page":"153-164","update-policy":"https:\/\/doi.org\/10.4093\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Elucidating the Epigenetic Landscape of Type 2 Diabetes Mellitus: A Multi-Omics Analysis Revealing Novel CpG Sites and Their Association with Cardiometabolic 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