ArticleProceedings of the National Academy of Sciences of the United States of America2018
Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- Comparing bulk and single-cell methodologies and models to profile gene expression, chromatin accessibility and regulatory links in endothelial cells treated with TNFα.Biochemistry and biophysics reports · 2026Article
- Mechanosensitive FHL2 tunes endothelial function via microtubule-actomyosin crosstalk.The EMBO journal · 2026Article
- Epigenetic regulation in atherosclerosis and its therapeutic potential.Nature reviews. Cardiology · 2026Review
- Comparing bulk and single-cell methodologies and models to profile gene expression, chromatin accessibility and regulatory links in endothelial cells treated with TNFα.bioRxiv : the preprint server for biology · 2026Article
- Nanomedicine-based theranostics in atherosclerotic cardiovascular diseases.Journal of biomedical science · 2026Review
- Multi-omics data integration from patients with carotid stenosis illuminates key molecular signatures of atherosclerotic instability.Genome medicine · 2026Article
- CRISPR-Based Therapy for Ischemic Stroke: A Narrative Review.Cellular and molecular neurobiology · 2026Review
- Genetically supported mediators linking peripheral metabolism to cerebral ischemia: a multi-omics characterization of HMGCR, TLR4, and MMP9 in angina pectoris and stroke.Briefings in functional genomics · 2026Article
- Functional Genomics Link REST to Endothelial Plasticity and Atherosclerosis.Circulation research · 2026Article
- Mutational disruption of transcription factors binding and regulatory networks in a case of unexplained total fertilization failure.Journal of translational medicine · 2025Article
- A Novel Function of NaFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Genotype inference from aggregated chromatin accessibility data reveals genetic regulatory mechanisms.Genome biology · 2025Article
- Data-driven projections of candidate enhancer-activating SNPs in immune regulation.BMC genomics · 2025Article
- Genotype inference from aggregated chromatin accessibility data reveals genetic regulatory mechanisms.bioRxiv : the preprint server for biology · 2024Article
- Gene editing therapy for cardiovascular diseases.MedComm · 2024Review
- Coronary Artery Disease Risk Variant Dampens the Expression of CALCRL by Reducing HSF Binding to Shear Stress Responsive Enhancer in Endothelial Cells In Vitro.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- The Role of Endothelial Cells in Atherosclerosis: Insights from Genetic Association Studies.The American journal of pathology · 2024Review
- Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells.The Journal of cell biology · 2024Article
- Integrated systems biology approach identifies gene targets for endothelial dysfunction.Molecular systems biology · 2023Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Biomechanical cues dynamically control major cellular processes, but whether genetic variants actively participate in mechanosensing mechanisms remains unexplored. Vascular homeostasis is tightly regulated by hemodynamics. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constitutive activation of vascular endothelium contributing to atherosclerosis, the major cause of coronary artery disease (CAD) and ischemic stroke (IS). Conversely, unidirectional flow promotes quiescent endothelium. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as strongly associated with CAD/IS; however, the causal mechanism related to this locus remains unknown. Using statistical analyses, assay of transposase accessible chromatin with whole-genome sequencing (ATAC-seq), H3K27ac/H3K4me2 ChIP with whole-genome sequencing (ChIP-seq), and CRISPR interference in human aortic endothelial cells (HAECs), our results demonstrate that rs17114036, a common noncoding polymorphism at 1p32.2, is located in an endothelial enhancer dynamically regulated by hemodynamics. CRISPR-Cas9-based genome editing shows that rs17114036-containing region promotes endothelial quiescence under unidirectional shear stress by regulating phospholipid phosphatase 3 (PLPP3). Chromatin accessibility quantitative trait locus (caQTL) mapping using HAECs from 56 donors, allelic imbalance assay from 7 donors, and luciferase assays demonstrate that CAD/IS-protective allele at rs17114036 in PLPP3 intron 5 confers increased endothelial enhancer activity. ChIP-PCR and luciferase assays show that CAD/IS-protective allele at rs17114036 creates a binding site for transcription factor Krüppel-like factor 2 (KLF2), which increases the enhancer activity under unidirectional flow. These results demonstrate that a human SNP contributes to critical endothelial mechanotransduction mechanisms and suggest that human haplotypes and related
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