Table 2.

EWAS and diabetes complications in humans

Tissue	Context	Epigenetic mechanism	Key Finding	Reference
Human Renal Tubuli	Nephropathy	DNA methylation	Altered DNA methylation at loci involved in fibrosis in tubuli from humans with diabetic nephropathy and renal dysfunction.	[87]
Peripheral blood samples	Nephropathy	DNA methylation	Specific DNA methylation changes associated with eGFR identified, and a distinct subset of these also associated with kidney fibrosis and showed concordant DNA methylation changes in the kidney cortex biopsies from patients with chronic kidney disease.	[88]
Peripheral blood leukocytes	Nephropathy	DNA methylation	Key DNA methylation changes associated with decline of renal function (estimated glomerular filtration rate (eGFR)) identified in the context of diabetic nephropathy, in a cohort of Pima Indians with T2D.	[89]
Primary vascular endothelial cells	Vascular complications	Histone acetylation (activating), DNA methylation	Hyperglycemia mediated induction of genes associated with endothelial dysfunction occurs via histone acetylation, and is inversely correlated with DNA methylation.	[90]
Human monocytes (Primary and THP-1 cells)	Effect of hyperglycemia	Activating And repressive histone modifications	Chronic hyperglycemia can alter the chromatin states to drive changes in expression of key genes associated with inflammation.	[93]
Vascular smooth muscle cells from diabetic mice	Vascular complications, metabolic memory	Histone methylation (repressive)	Dysregulation of epigenetic states is a key mechanism underlying metabolic memory, as well as inflammation in vascular cells.	[94]
Human blood monocytes and lymphocytes	Metabolic memory	Histone modifications	Monocyte histone acetylation was associated with HbA1c level during the DCCT phase and the long-term (EDIC) follow-up, pointing to an epigenetic basis for metabolic memory.	[103]
Human whole blood and blood monocytes	Metabolic memory	DNA methylation	Several key genes associated with complications display sustained differential DNA methylation patterns in the same diabetic subjects over 16 years in association with HbA1c and an adverse diabetes complications outcome.	[104]