Jinying Zhao1, Qiang An2, Jack Goldberg3, Arshed A Quyyumi4, Viola Vaccarino5. 1. Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA. Electronic address: jzhao5@tulane.edu. 2. Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA. 3. Seattle Epidemiologic Research and Information Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA. 4. Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA. 5. Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA; Department of Epidemiology, School of Public Health, Emory University, Atlanta, GA, USA.
Abstract
OBJECTIVE: Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a marker of early atherosclerosis. Glucocorticoid receptor gene (NR3C1) regulates many biological processes, including stress response, behavioral, cardiometabolic and immunologic functions. Genetic variants in NR3C1 have been associated with atherosclerosis and related risk factors. This study investigated the association of NR3C1 promoter methylation with FMD, independent of genetic and family-level environmental factors. METHODS: We studied 84 middle-aged, male-male monozygotic twin pairs recruited from the Vietnam Era Twin Registry. Brachial artery FMD was measured by ultrasound. DNA methylation levels at 22 CpG residues in the NR3C1 exon 1F promoter region were quantified by bisulfite pyrosequencing in genomic DNA isolated from peripheral blood leukocytes. Co-twin control analyses were conducted to examine the association of methylation variation with FMD, adjusting for smoking, physical activity, body mass index, lipids, blood pressure, fasting glucose, and depressive symptoms. Multiple testing was corrected using the false discovery rate. RESULTS: Mean methylation level across the 22 studied CpG sites was 2.02%. Methylation alterations at 12 out of the 22 CpG residues were significantly associated with FMD. On average, a 1% increase in the intra-pair difference in mean DNA methylation was associated with 2.83% increase in the intra-pair difference in FMD (95% CI: 1.46-4.20; P < 0.0001) after adjusting for risk factors and multiple testing. CONCLUSION: Methylation variation in NR3C1 exon 1F promoter significantly influences subclinical atherosclerosis, independent of genetic, early family environmental and other risk factors.
OBJECTIVE: Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a marker of early atherosclerosis. Glucocorticoid receptor gene (NR3C1) regulates many biological processes, including stress response, behavioral, cardiometabolic and immunologic functions. Genetic variants in NR3C1 have been associated with atherosclerosis and related risk factors. This study investigated the association of NR3C1 promoter methylation with FMD, independent of genetic and family-level environmental factors. METHODS: We studied 84 middle-aged, male-male monozygotic twin pairs recruited from the Vietnam Era Twin Registry. Brachial artery FMD was measured by ultrasound. DNA methylation levels at 22 CpG residues in the NR3C1 exon 1F promoter region were quantified by bisulfite pyrosequencing in genomic DNA isolated from peripheral blood leukocytes. Co-twin control analyses were conducted to examine the association of methylation variation with FMD, adjusting for smoking, physical activity, body mass index, lipids, blood pressure, fasting glucose, and depressive symptoms. Multiple testing was corrected using the false discovery rate. RESULTS: Mean methylation level across the 22 studied CpG sites was 2.02%. Methylation alterations at 12 out of the 22 CpG residues were significantly associated with FMD. On average, a 1% increase in the intra-pair difference in mean DNA methylation was associated with 2.83% increase in the intra-pair difference in FMD (95% CI: 1.46-4.20; P < 0.0001) after adjusting for risk factors and multiple testing. CONCLUSION: Methylation variation in NR3C1 exon 1F promoter significantly influences subclinical atherosclerosis, independent of genetic, early family environmental and other risk factors.
Authors: Viola Vaccarino; Durreshahwar Khan; John Votaw; Tracy Faber; Emir Veledar; Dean P Jones; Jack Goldberg; Paolo Raggi; Arshed A Quyyumi; J Douglas Bremner Journal: J Am Coll Cardiol Date: 2011-03-15 Impact factor: 24.094
Authors: Alexandra E Shields; Lauren A Wise; Edward A Ruiz-Narvaez; Bobak Seddighzadeh; Hyang-Min Byun; Yvette C Cozier; Lynn Rosenberg; Julie R Palmer; Andrea A Baccarelli Journal: Epigenomics Date: 2016-09-13 Impact factor: 4.778
Authors: M Austin Argentieri; Sairaman Nagarajan; Bobak Seddighzadeh; Andrea A Baccarelli; Alexandra E Shields Journal: EBioMedicine Date: 2017-04-04 Impact factor: 8.143