Abstract 53: Transcriptomics and Methylomics of Atherosclerosis in Circulating Monocytes - the Multi-Ethnic Study of Atherosclerosis
Little is known regarding the transcriptional and epigenetic basis for atherogenesis and cardiovascular disease (CVD) risk. Here we integrate transcriptomic (Illumina HumanHT-12 v4) and methylomic (Illumina 450K array) data from purified monocytes with concurrent CVD risk factors and measures of atherosclerosis - carotid plaque (CP) identified using ultrasound and coronary artery calcium (CAC), from 1,208 randomly selected participants (554 whites, 260 blacks, 394 Hispanics) of the Multi-Ethnic Study of Atherosclerosis (MESA). Association analysis was performed using linear and logistic regression, adjusting for demographics, technical covariates, and other known CVD risk factors. A false discovery rate (FDR) <0.05 was used to control for multiple comparisons.
RESULTS: We identified expression of two genes, ARID5B (a transcription factor) and PDLIM7, positively associated with both CP and CAC, and 17 additional genes associated with only CAC. We also identified 29 and seven differentially methylated CpGs associated with CP and CAC, respectively, including a CpG at ILVBL associated with both CP and CAC. Eleven of these atherosclerosis CpGs were also associated with cis-gene expression, including an ARID5B expression-associated methylation site (cg25953130, ARID5B intron) which overlapped a predicted strong enhancer, a transcription factor binding site (for EP300), and a DNase I hotspot (ENCODE and BLUEPRINT monocyte data). The inverse association between methylation of this ARID5B CpG and atherosclerosis (CP:p=4.3x10-7, FDR=0.01; CAC: p= 2.4x10-5, FDR=0.32) appeared to be mediated through ARID5B expression (CP: p=2.1x10-4, CAC: p=2.1 x10-3, using Structural Equation modeling with bootstrapping). Furthermore, many other known risk factors for CVD (age, ethnicity, body mass index, diabetes, HDL, and interleukin-6 levels) were also associated with ARID5B expression at genome-wide levels of significance. The ARID5B associations with atherosclerosis at gene expression and methylation levels together explain an additional 2.3% variability in CP above and beyond known CVD risk factors, and were consistent across age (< or ≥65 years), sex, race/ethnicity, CVD status, or statin use subgroups, as well as the independent sites of data collection. ARID5B expression was also positively associated with prevalent CVD (p=0.006).
CONCLUSIONS: The concurrent multi-omic profiling of atherogenic-related cells coupled with state-of-the-art measurements of atherosclerosis in a large, well-phenotyped, multi-ethnic cohort provide novel insights into the biomarkers and the potential molecular mechanisms of atherosclerosis. In particular, our data on ARID5B, taken together with previously reported experimental evidence for its role in promoting lipid accumulation and smooth muscle cell differentiation, strongly suggests an atherogenic role for this gene.
Author Disclosures: Y. Liu: None. J. Ding: None. L.M. Reynolds: None. J.R. Taylor: None. K. Lohman: None. D. Siscovick: None. S.S. Rich: None. B.M. Psaty: None. J.D. Kaufman: None. G. Burke: None. S. Shea: None. D.R. Jacobs: None. J.H. Stein: None. I. Hoeschele: None. R.P. Tracy: None. W. Post: None. D.M. Herrington: None.
- © 2015 by American Heart Association, Inc.