DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease

作者：Lucy Sinke, Thomas Delerue, Rory Wilson, Xueling Lu, Yujing Xia, Ricardo Costeira, M. Kamal Nasr, Marian Beekman, Lude Franke, Alexandra Zhernakova, Jingyuan Fu, Christian Gieger, Christian Herder, Wolfgang Köenig, Annette Peters, José M. Ordovás, Marcus Dörr, Hans J. Grabe, Matthias Nauck, Jordana T. Bell, Alexander Teumer, Harold Snieder, Mélanie Waldenberger, P. Eline Slagboom, Bastiaan T. Heijmans · 发表于：Diabetologia · 年份：2025 · DOI：10.1007/s00125-025-06549-6 · 被引用次数：6 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Epigenetics and DNA Methylation、Kruppel-like factors research

AIMS/HYPOTHESIS: Despite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk. METHODS: We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods. RESULTS: Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin lev...