Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk

Quertermous, Thomas; Li, Daniel Yuhang; Weldy, Chad S.; Ramste, Markus; Sharma, Disha; Monteiro, João P.; Gu, Wenduo; Worssam, Matthew D.; Palmisano, Brian T.; Park, Chong Y.; Cheng, Paul

doi:10.1161/atvbaha.123.319480

Cited by 3 publications

(1 citation statement)

References 27 publications

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“…Several groups have performed integrative epigenetic analyses in CASMC to identify genes linked to coronary artery disease (CAD) 63,90,[96][97][98][99][100] , but these studies have not performed a comprehensive mapping of promoters and enhancers in distinct phenotypic states. One study used brief six-hour TGFβ or PDGF treatments combined ATAC-seq with GWAS data to identify regulatory regions associated with CAD risk 63 .…”

Section: Human Coronary Artery Smooth Muscle Cells Exhibit a Distinct...mentioning

confidence: 99%

Epigenetic Remodeling in Human Coronary Artery Smooth Muscle Cell Phenotypic Switching

Chakraborty,

Schulz,

Lezon-Geyda

et al. 2024

Preprint

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Background: Smooth muscle cell (SMC) dedifferentiation contributes to repair and remodeling, but also cardiovascular pathologies. To understand this plasticity, the epigenetic landscape in SMC phenotypic switching was profiled. Methods: Genome-wide analyses of histone modifications (ChIP-seq), chromatin architecture (ATAC-seq), and transcriptomes (RNA-seq) were performed on human coronary artery SMCs (CASMC) treated with rapamycin (contractile phenotype) and PDGF-BB (synthetic phenotype). Results: Analyses of differentially acetylated promoter regions identified ZEB and ZBT7A as novel enriched regulatory motifs. There were more changes in the enhancer epigenome than in promoters in CASMC phenotypic switching. Rapamycin-activated enhancers were associated with differentiation and TGF-beta signaling pathways and were most enriched in TEAD, SRF and SMAD motifs, whereas PDGF-induced enhancers were associated with ERK signaling and migration pathways, and were most enriched in ETV4, SOX5, and FOS motifs. GATA, TEAD, and SMCA1 motifs were enriched in CASMC enhancer open chromatin compared to other cell types. Candidate enhancers with single nucleotide polymorphisms linked to cardiovascular disease were markedly enriched in active enhancers and super enhancers and showed significant activity in reporter assays. In CASMC promoters and enhancers, common regulatory motifs were often enriched in both the differentiated and dedifferentiated phenotypes, suggesting that differential cofactor binding, as occurs with SRF at CArG elements, may be a more widespread mechanism underlying phenotypic switching. Conclusions: These data identify novel regulatory elements engaged in SMC phenotypic switching and provide a comprehensive profile of SMC promoters, enhancers, super enhancers, and chromatin accessibility as a significant resource for studies of CASMC phenotype.

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Section: Human Coronary Artery Smooth Muscle Cells Exhibit a Distinct...mentioning

confidence: 99%

Epigenetic Remodeling in Human Coronary Artery Smooth Muscle Cell Phenotypic Switching

Chakraborty,

Schulz,

Lezon-Geyda

et al. 2024

Preprint

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Spatial transcriptomic mapping of coronary atherosclerosis in the luminal plaque and beyond

Cheng,

Quertermous

2025

Nat Cardiovasc Res

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Omics Science and Social Aspects in Detecting Biomarkers for Diagnosis, Risk Prediction, and Outcomes of Carotid Stenosis

Costa,

Scalise,

Ielapi

et al. 2024

Biomolecules

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Carotid stenosis is characterized by the progressive narrowing of the carotid arteries due to the formation of atherosclerotic plaque, which can lead to stroke and death as major complications. Numerous biomarkers allow for its study and characterization, particularly those related to “omics” sciences. Through the most common research databases, we report representative studies about carotid stenosis biomarkers based on genomics, transcriptomics, proteomics, and metabolomics in a narrative review. To establish a priority among studies based on their internal validity, we used a quality assessment tool, the Scale for the Assessment of Narrative Review Articles (SANRA). Genes, transcriptomes, proteins, and metabolites can diagnose the disease, define plaque connotations, predict consequences after revascularization interventions, and associate carotid stenosis with other patient comorbidities. It also emerged that many aspects determining the patient’s psychological and social sphere are implicated in carotid disease. In conclusion, when taking the multidisciplinary approach that combines human sciences with biological sciences, it is possible to comprehensively define a patient’s health and thus improve their clinical management through precision medicine.

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Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk

Cited by 3 publications

References 27 publications

Epigenetic Remodeling in Human Coronary Artery Smooth Muscle Cell Phenotypic Switching

Epigenetic Remodeling in Human Coronary Artery Smooth Muscle Cell Phenotypic Switching

Spatial transcriptomic mapping of coronary atherosclerosis in the luminal plaque and beyond

Omics Science and Social Aspects in Detecting Biomarkers for Diagnosis, Risk Prediction, and Outcomes of Carotid Stenosis

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