Abstract 15715: Dna Methylation of Genes Involved in Inflammation Correlates With Cardiometabolic Function in Morbidly Obese Adults

Abstract

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated impaired vascular function that correlated with global DNA hypomethylation in adipose tissue (AT) isolated from obese adults (OB). Blood-detected epigenetic profiles may serve as non-invasive clinically relevant biomarkers and stand as an unexploited precision medicine reserve. Hypothesis: We hypothesized a contributing role of DNA methylation to systemic inflammation in OB subjects compared to lean controls (CON). We also explored the correlation between these methylation profiles and cardiometabolic measurements. Methods: We obtained blood and AT samples from bariatric patients (n=24; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and CON adults (n=24; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for flow-induced dilation (FID), nitric oxide (NO) and reactive oxygen species (ROS) production. Brachial artery flow-mediated dilation (FMD) was measured via Doppler ultrasound. Promoter methylation of 94 genes involved in inflammation and autoimmunity (EpiTect Methyl II PCR Arrays) were analyzed in whole-blood DNA in relation to vascular function and cardiometabolic risk factors. Results: 70% of genes had a higher methylated fraction in CON compare to only 28% in OB subjects. After correction for multiple testing, 28 genes were significantly hypermethylated in CON compared to OB; on top of these genes are CXCL1, CXCL12, CXCL6, EGR1, HDAC4, IGF2BP2, IL12A, IL12B, and IL17RA. Ten of these genes had significantly higher mRNA in OB compared to CON indicating the functional impact of such signals on gene transcription; on top of these genes are CXCL6, TLR5, IL6ST, IL15RA, and HDAC4. Methylation % of differentially methylated genes inversely correlated with BMI, total fat %, visceral fat%, blood pressure, fasting plasma insulin, serum IL6 and CRP (C-reactive protein), arteriolar ROS, and alcohol consumption and positive correlations with lean %, HDL, plasma folate and vitamin B12, arteriolar FID and NO production, and brachial FMD. Conclusions: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation. A downstream target for this pathway could reside in endothelial cells resulting in vascular dysfunction