Abstract
There is emerging evidence of an association between epigenetic modifications, glycemic control and atherosclerosis risk. In this study, we mapped genome-wide epigenetic changes in patients with type 2 diabetes (T2D) and advanced atherosclerotic disease. We performed chromatin immunoprecipitation sequencing (ChIP-seq) using a histone 3 lysine 9 acetylation (H3K9ac) mark in peripheral blood mononuclear cells from patients with atherosclerosis with T2D (n = 8) or without T2D (ND, n = 10). We mapped epigenome changes and identified 23,394 and 13,133 peaks in ND and T2D individuals, respectively. Out of all the peaks, 753 domains near the transcription start site (TSS) were unique to T2D. We found that T2D in atherosclerosis leads to an H3K9ac increase in 118, and loss in 63 genomic regions. Furthermore, we discovered an association between the genomic locations of significant H3K9ac changes with genetic variants identified in previous T2D GWAS. The transcription factor 7-like 2 (TCF7L2) rs7903146, together with several human leukocyte antigen (HLA) variants, were among the domains with the most dramatic changes of H3K9ac enrichments. Pathway analysis revealed multiple activated pathways involved in immunity, including type 1 diabetes. Our results present novel evidence on the interaction between genetics and epigenetics, as well as epigenetic changes related to immunity in patients with T2D and advanced atherosclerotic disease.
Highlights
To study the role of H3K9ac in atherosclerosis patients with type 2 diabetes (T2D), we profiled the genome-wide enrichment of H3K9ac by Chromatin Immunoprecipitation (ChIP)-seq in the peripheral blood mononuclear cells (PBMCs) collected from patients with T2D (n = 8) or without T2D (ND, n = 10), all with advanced atherosclerotic disease
Our study presents the first genome-wide profile of histone acetylation in humans affected with atherosclerosis and T2D
We performed ChIP-seq on PBMCs and traced the natural changes in how the T2D condition affects the epigenetic profile of atherosclerosis
Summary
Atherosclerosis accounts for more than 80% of deaths among patients with diabetes. Strong evidence from large treatment studies, such as the United Kingdom Prospective 4.0/). Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT), supports an association between glycemic control and cardiovascular disease (CVD) risk [1,2]. Animal and human studies have provided further evidence that prolonged exposure to hyperglycemia induces alterations in vascular tissue that potentially accelerate the atherosclerotic process [3,4]. The atherogenic role of glucose involves protein and lipid glycosylation relevant to the atherosclerotic process, oxidative stress and protein kinase C (PKC) activation [5]. There is emerging evidence of associations between epigenetic modifications and atherosclerosis risk
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