Abstract P259: Genome-Wide DNA Methylation and Subclinical Cardiovascular Disease in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Background: Coronary artery calcification (CAC) and carotid intima-media thickness (CIMT), established measures of subclinical atherosclerosis, that have been demonstrated to improve prediction of coronary artery disease (CAD) risk beyond classical risk factors (CRFs). This study examined the epigenetic mechanisms underlying the appearance of CAC and increased CIMT, which have not been previously explored.
Methods: We conducted an epigenome-wide association study (EWAS) in 46 non-smoking and non-diabetic white subjects randomly selected from the Coronary Artery Risk Development in Young Adults (CARDIA) study. CAC and CIMT were measured by computed tomography (CT) and catotid artery ultrasound at examination year (Y) 20. The Illumina HumanMethylation450 BeadChip was used to measure DNA methylation in white blood cells collected at Y15. We dropped one sample with >1% of the CpG sites having a detection p-value >0.05 and then exclude ~160k CpG probes due to their ambiguously mapping to the genome or with the presence of common SNPs, etc. Both background adjustment and normalization were performed separately for Infinium I and II probes, and new values were calculated and then transformed into M-values. After correction for potential chip effect, we examined the associations between these pre-processed methylation levels at each CpG site with CAC and CIMT using multiple logistic and linear regression models, respectively. Pathway analysis was performed to explore the gene sets that were significantly associated with CAC and CIMT.
Results: Several CpG sites in multiple genes were significantly associated with CAC or CIMT. Some of these genes play roles in the regulation of vascular function, such as ion binding and transport (HRH1, LRP1B, KCNJ9, TRIM40, ADAMTS3 for CAC and BRSK2, ZNF428, TROVE2, C1orf86 for CIMT) and metabolic processes (LEPR for CAC and NUP50 for CIMT). Pathway analyses revealed several common canonical pathways for CAC and CIMT including, calcium signaling, axon guidance, and focal adhesion etc., which are relevant to the occurrence of these two subclinical CADs. The statistical significance of identified CpG sties for either CAC or CIMT did not remain after correction for multiple testing, possibly due to the small sample size.
Conclusion: Our preliminary findings suggest that methylomic mechanisms may play a role in the development of CAC and CIMT, and subsequently the etiology of CAD. Future replication studies in larger longitudinally studies are needed.
Author Disclosures: L. Hou: None. X. Liu: None. Y. Zheng: None. W. Zhang: None. X. Zhang: None. H. Ning: None. J. Carr: None. M. Fornage: None. K. He: None. K. Liu: None. D.M. LIoyd-Jones: None.
- © 2014 by American Heart Association, Inc.