Dataset Information

DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroni del COR).

ABSTRACT: OBJECTIVE:The objectives of this study were to decipher whether age-independent cardiovascular risk is associated with DNA methylation at 5'-cytosine-phosphate-guanine-3' (CpG) level and to determine whether these differential methylation signatures are associated with the incidence of cardiovascular events. APPROACH AND RESULTS:We designed a 2-stage, cross-sectional, epigenome-wide association study. Age-independent cardiovascular risk calculation was based on vascular age and on the residuals of the relationship between age and cardiovascular risk. Blood DNA methylomes from 2 independent populations were profiled using the Infinium HumanMethylation450 BeadChip. The discovery stage of these studies was performed in the REGICOR cohort (REgistre GIroní del COR; n=645). Next, we validated the initial findings in the Framingham Offspring Study (n=2542). Eight CpGs located in 4 genes (AHRR, CPT1A, PPIF, and SBNO2) and 3 intergenic regions showed differential methylation in association with age-independent cardiovascular risk (P?1.17×10-7). These CpGs explained 12.01% to 15.16% of the variability of age-independent cardiovascular risk in REGICOR and 7.51% to 8.53% in Framingham Offspring Study. Four of them were only related to smoking, 3 were related to smoking and body mass index, and 1 to diabetes mellitus, triglycerides levels, and body mass index (P?7.81×10-4). In addition, we developed methylation risk scores based on these CpGs and observed an association between these scores and cardiovascular disease incidence (hazard ratio=1.32; 95% confidence interval: 1.16-1.51). CONCLUSIONS:Age-independent cardiovascular risk was related to different DNA methylation profiles, with 8 CpGs showing differential methylation patterns. Most of these CpGs were associated with smoking, and 3 of them were also related to body mass index. Risk scores based on these differential methylation patterns were associated with cardiovascular events and could be useful predictive indices.

SUBMITTER: Fernandez-Sanles A

PROVIDER: S-EPMC5823770 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroní del COR).

Fernández-Sanlés Alba A Sayols-Baixeras Sergi S Curcio Santiago S Subirana Isaac I Marrugat Jaume J Elosua Roberto R

Arteriosclerosis, thrombosis, and vascular biology 20180111 3

<h4>Objective</h4>The objectives of this study were to decipher whether age-independent cardiovascular risk is associated with DNA methylation at 5'-cytosine-phosphate-guanine-3' (CpG) level and to determine whether these differential methylation signatures are associated with the incidence of cardiovascular events.<h4>Approach and results</h4>We designed a 2-stage, cross-sectional, epigenome-wide association study. Age-independent cardiovascular risk calculation was based on vascular age and on ...[more]

PMID: 29326313

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Project description:BackgroundDevelopment of cardiovascular disease (CVD), including coronary artery disease, arrhythmia, and ischemic stroke, depends on environmental and genetic factors. To investigate the epigenetic basis of myocardial infarction (MI), we performed an epigenome-wide association study for this condition in elderly Japanese subjects. A total of 192 case subjects with MI and 192 control subjects were recruited from hospital attendees and the general population, respectively. Genome-wide DNA methylation (DNAm) profiles for DNA isolated from whole blood were obtained by analysis with an Infinium HumanMethylation450 BeadChip. The relation of DNAm sites found to be significantly associated with MI to nearby single nucleotide polymorphisms (SNPs) previously shown to be associated with CVD was assessed in the control group.FindingsThree DNAm sites (cg06642177, cg07786668, cg17218495) showed genome-wide significant associations with MI (p = 4.33 × 10-8, 3.96 × 10-10, and 3.77 × 10-8, respectively). Two of these sites (cg07786668, cg17218495) still showed such associations after adjustment for classical risk factors of MI (p = 1.04 × 10-7 and 6.60 × 10-8, respectively). The DNAm sites cg07786668 and cg17218495 are located in ZFHX3 (zinc finger homeobox 3) and SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4) genes, respectively. SNPs in ZFHX3 or SMARCA4 that were previously found to be associated with CVD were not significantly associated with these DNAm sites in our control subjects.ConclusionsWe identified two DNAm sites-cg07786668 in ZFHX3 and cg17218495 in SMARCA4- that are independently and significantly associated with MI. Our results suggest that the development of MI might be influenced by changes in DNAm at these sites via a pathway that differs from that affected by CVD-associated SNPs in these genes. The Kita-Nagoya Genomic Epidemiology (KING) study, which was the source of control samples in the present study, was registered in ClinicalTrials.gov (NCT00262691) on 6 December 2005.

Project description:BackgroundCocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue.MethodsWe investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of Brodmann area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study (EWAS) and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology (GO) enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age.ResultsWhile no cytosine-phosphate-guanine (CpG) site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified Neuropeptide FF Receptor 2 (NPFFR2) and Kalirin RhoGEF Kinase (KALRN) for which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction (PPI) networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit (JUN). In BA9, we observed a trend toward epigenetic age acceleration (EAA) in individuals with CUD remaining stable even after adjustment for covariates.ConclusionResults from our study highlight that CUD is associated with epigenome-wide differences in DNAm levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex (PFC). Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.

Dataset Information

DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroni del COR).

Publications

DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroní del COR).

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