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000282598 1001_ $$00000-0002-9209-1266$$aSinke, Lucy$$b0
000282598 245__ $$aDNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease.
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000282598 520__ $$aDespite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.
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000282598 650_7 $$2Other$$aAdiponectin
000282598 650_7 $$2Other$$aCausal inference
000282598 650_7 $$2Other$$aEpigenomics
000282598 650_7 $$2Other$$aLeptin
000282598 650_7 $$2Other$$aLipid metabolism
000282598 650_7 $$2Other$$aMeta-analysis
000282598 650_7 $$2Other$$aMetabolic health
000282598 650_7 $$2Other$$aType 2 diabetes
000282598 650_7 $$2NLM Chemicals$$aAdiponectin
000282598 650_7 $$2NLM Chemicals$$aLeptin
000282598 650_2 $$2MeSH$$aHumans
000282598 650_2 $$2MeSH$$aAdiponectin: blood
000282598 650_2 $$2MeSH$$aAdiponectin: genetics
000282598 650_2 $$2MeSH$$aAdiponectin: metabolism
000282598 650_2 $$2MeSH$$aDNA Methylation: genetics
000282598 650_2 $$2MeSH$$aLipid Metabolism: genetics
000282598 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: genetics
000282598 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: metabolism
000282598 650_2 $$2MeSH$$aLeptin: blood
000282598 650_2 $$2MeSH$$aLeptin: genetics
000282598 650_2 $$2MeSH$$aCpG Islands: genetics
000282598 650_2 $$2MeSH$$aMetabolic Diseases: genetics
000282598 650_2 $$2MeSH$$aMetabolic Diseases: metabolism
000282598 650_2 $$2MeSH$$aGenome-Wide Association Study
000282598 650_2 $$2MeSH$$aFemale
000282598 650_2 $$2MeSH$$aMale
000282598 7001_ $$00000-0002-6725-5361$$aDelerue, Thomas$$b1
000282598 7001_ $$00000-0001-6135-3764$$aWilson, Rory$$b2
000282598 7001_ $$00000-0001-6067-7361$$aLu, Xueling$$b3
000282598 7001_ $$00000-0002-7746-9646$$aXia, Yujing$$b4
000282598 7001_ $$00000-0002-8316-5219$$aCosteira, Ricardo$$b5
000282598 7001_ $$00009-0004-2816-7168$$aNasr, M Kamal$$b6
000282598 7001_ $$00000-0003-0585-6206$$aBeekman, Marian$$b7
000282598 7001_ $$00000-0002-5159-8802$$aFranke, Lude$$b8
000282598 7001_ $$00000-0002-4574-0841$$aZhernakova, Alexandra$$b9
000282598 7001_ $$00000-0001-5578-1236$$aFu, Jingyuan$$b10
000282598 7001_ $$00000-0001-6986-9554$$aGieger, Christian$$b11
000282598 7001_ $$00000-0002-2050-093X$$aHerder, Christian$$b12
000282598 7001_ $$00000-0002-2064-9603$$aKoenig, Wolfgang$$b13
000282598 7001_ $$00000-0001-6645-0985$$aPeters, Annette$$b14
000282598 7001_ $$00000-0002-7581-5680$$aOrdovas, José M$$b15
000282598 7001_ $$00000-0001-7471-475X$$aDörr, Marcus$$b16
000282598 7001_ $$0P:(DE-2719)2811781$$aGrabe, Hans J$$b17
000282598 7001_ $$00000-0002-6678-7964$$aNauck, Matthias$$b18
000282598 7001_ $$00000-0002-3858-5986$$aBell, Jordana T$$b19
000282598 7001_ $$00000-0002-8309-094X$$aTeumer, Alexander$$b20
000282598 7001_ $$00000-0003-1949-2298$$aSnieder, Harold$$b21
000282598 7001_ $$00000-0003-0583-5093$$aWaldenberger, Melanie$$b22
000282598 7001_ $$00000-0002-2875-4723$$aSlagboom, P Eline$$b23
000282598 7001_ $$00000-0001-5918-0534$$aHeijmans, Bastiaan T$$b24
000282598 773__ $$0PERI:(DE-600)1458993-X$$a10.1007/s00125-025-06549-6$$gVol. 69, no. 1, p. 127 - 145$$n1$$p127 - 145$$tDiabetologia$$v69$$x0012-186X$$y2026
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