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Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study.

ABSTRACT: DNA methylation is an important epigenetic modification that has been implicated in the pathogenesis of atherosclerosis. Although previous studies have identified various CpG sites and genes whose methylation is associated with atherosclerosis in populations with European or Mexican ancestry, the genome?wide pattern of DNA methylation in the atherosclerotic human aorta is yet to be elucidated in Japanese individuals. In the present study, a genome?wide analysis of DNA methylation at ~853,000 CpG sites was performed using 128 postmortem aortic intima specimens obtained from 64 Japanese patients. To avoid the effects of interindividual variation, intraindividual paired comparisons were performed between atheromatous plaque lesions and corresponding plaque?free tissue for each patient. Bisulfite?modified genomic DNA was analyzed using a specific microarray for DNA methylation. DNA methylation at each CpG site was calculated as the ? value, where ? = (intensity of the methylated allele)/(intensity of the methylated allele?+?intensity of the unmethylated allele?+?100). Bonferroni's correction for statistical significance of association was applied to compensate for multiple comparisons. The methylation of 2,679 CpG sites differed significantly (P<5.86x10?8) between atheromatous plaque lesions and the corresponding plaque?free intima, with 2,272 and 407 CpG sites in atheromatous plaques being hyper? or hypomethylated, respectively. A total of 5 hypermethylated CpG sites in atheromatous plaques were demonstrated to have a difference in ? value of >0.15 (plaque lesion?plaque?free intima) and 11 had a ? ratio of >1.50 (plaque/plaque?free intima). A further 15 and 17 hypomethylated CpG sites in atheromatous plaques were observed to have a difference in ? value of

SUBMITTER: Yamada Y

PROVIDER: S-EPMC5846673 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study.

Yamada Yoshiji Y Horibe Hideki H Oguri Mitsutoshi M Sakuma Jun J Takeuchi Ichiro I Yasukochi Yoshiki Y Kato Kimihiko K Sawabe Motoji M

International journal of molecular medicine 20180202 5

DNA methylation is an important epigenetic modification that has been implicated in the pathogenesis of atherosclerosis. Although previous studies have identified various CpG sites and genes whose methylation is associated with atherosclerosis in populations with European or Mexican ancestry, the genome‑wide pattern of DNA methylation in the atherosclerotic human aorta is yet to be elucidated in Japanese individuals. In the present study, a genome‑wide analysis of DNA methylation at ~853,000 CpG ...[more]

PMID: 29436575

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Project description:BackgroundEpigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis.ResultsStage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.ConclusionsThis study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.

Project description:ObjectiveThis study identified underlying genetic molecules associated with histologically unstable carotid atherosclerotic plaques through bioinformatics analysis that may be potential biomarkers and therapeutic targets.MethodsThree transcriptome datasets (GSE41571, GSE120521 and E-MTAB-2055) and one non-coding RNA dataset (GSE111794) that met histological grouping criteria of unstable plaque were downloaded. The common differentially expressed genes (co-DEGs) of unstable plaques identified from three mRNA datasets were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG). A protein-protein interaction (PPI) network was constructed to present the interaction between co-DEGs and screen out hub genes. MiRNet database and GSE111794 dataset were used to identify the miRNAs targeting hub genes. Associated transcription factors (TFs) and drugs were also predicted. These predicted results were used to construct miRNA/TFs-hub gene and drug-hub gene regulatory networks.ResultsA total of 105 co-DEGs were identified, including 42 up-regulated genes and 63 down-regulated genes, which were mainly enriched in collagen-containing extracellular matrix, focal adhesion, actin filament bundle, chemokine signaling pathway and regulates of actin cytoskeleton. Ten hub genes (up-regulated: HCK, C1QC, CD14, FCER1G, LCP1 and RAC2; down-regulated: TPM1, MYH10, PLS3 and FMOD) were screened. HCK and RAC2 were involved in chemokine signaling pathway, MYH10 and RAC2 were involved in regulation of actin cytoskeleton. We also predicted 12 miRNAs, top5 TFs and 25 drugs targeting hub genes. In the miRNA/TF-hub gene regulatory network, PLS3 was the most connected hub genes and was targeted by six miRNAs and all five screened TFs. In the drug-hub gene regulatory network, HCK was targeted by 20 drugs including 10 inhibitors.ConclusionsWe screened 10 hub genes and predicted miRNAs and TFs targeting them. These molecules may play a crucial role in the progression of histologically unstable carotid plaques and serve as potential biomarkers and therapeutic targets.

Dataset Information

Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study.

Publications

Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study.

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