Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

Adlam, David; Olson, Timothy M.; Combaret, Nicolas; Kovacic, Jason C.; Iismaa, Siiri E.; Al-hussaini, Abtehal; O’Byrne, Megan M.; Bouajila, Sara; Georges, Adrien; Mishra, Ketan; Braund, Peter S.; d’Escamard, Valentina; Huang, Shizheng; Margaritis, Marios; Nelson, Christopher P.; Andrade, Mariza de; Kadian-Dodov, Daniella; Welch, Catherine; Mazurkiewicz, Stephani; Jeunemaı̂tre, Xavier; Won, Hong-Hee; Giannoulatou, Eleni; Sweeting, Michael; Müller, D.; Wood, Alice; McGrath-Cadell, Lucy; Fatkin, Diane; Dunwoodie, Sally L.; Harvey, Richard P.; Holloway, Catherine; Jp, Empana; Jouven, Xavier; Olin, Jeffrey W.; Gulati, Rajiv; Tweet, Marysia S.; Hayes, Sharonne N.; Samani, Nilesh J.; Graham, Robert M.; Motreff, Pascal; Bouatia-Naji, Nabila

doi:10.1016/j.jacc.2018.09.085

Cited by 159 publications

(95 citation statements)

References 46 publications

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“…Our study provides robust confirmation of the association with FMD of PHACTR1, a pleiotropic locus that is involved in a large number of vascular diseases 39,40 39 is not supported by our results, or those from consequent works that used an identical approach of iPSC induced endothelial cells 41 or measured endothelin-1 plasma levels in FMD patients and matched healthy controls 42 . On the other hand, the phosphatase and actin-binding protein encoded by PHACTR1 regulates actin stress fibre assembly and cell motility 43 , functions highly relevant to the cellular disorganization that characterizes VSMCs in multifocal FMD affected arteries 36 .…”

Section: Discussionmentioning

confidence: 45%

Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

Georges

Yang

Berrandou

et al. 2020

Preprint

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Fibromuscular dysplasia (FMD) is an arteriopathy that presents clinically by hypertension and stroke, mostly in early middle-aged women. We report results from the first genome-wide association meta-analysis of FMD including 1962 FMD cases and 7100 controls. We confirmed PHACTR1 and identified three new loci (LRP1, ATP2B1, and LIMA1) associated with FMD. Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). FMD associated variants were located in arterial-specific enhancers active in vascular smooth muscle cells and fibroblasts. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. Cross-trait linkage disequilibrium analyses identified positive genetic correlations with blood pressure, migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independent from the genetics of blood pressure.

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Section: Discussionmentioning

confidence: 45%

Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

Georges

Yang

Berrandou

et al. 2020

Preprint

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“…However, no signi cant difference in Ccl2 expression was detected between HLHS and controls. Edn1 (Endothelin 1) genetic locus is correlated to spontaneous coronary artery dissection [35]. It was highly expressed in LV/RV HLHS compared to controls in mice, and was highly expressed in RV HLHS than control neonates.…”

Section: Discussionmentioning

confidence: 99%

Exploration and Validation of Hub Genes and Pathways in the Progression of Hypoplastic Left Heart Syndrome via Weighted Gene Co-Expression Network Analysis

Liu

Shang

et al. 2020

Preprint

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Objective: Despite significant progress in surgical treatment of hypoplastic left heart syndrome (HLHS), its mortality and morbidity are still high. Little is known about the molecular abnormalities of the syndrome. In this study, we aimed to probe into hub genes and key pathways in the progression of the syndrome.Methods: Differentially expressed genes (DEGs) were identified in left ventricle (LV) or right ventricle (RV) tissues between HLHS and controls using the GSE77798 dataset. Then, weighted gene co-expression network analysis (WGCNA) was performed and key modules were constructed for HLHS. Based on the genes in the key modules, protein-protein interaction (PPI) networks were conducted, and hub genes and key pathways were screened. Finally, the GSE23959 dataset was used to validate hub genes between HLHS and controls.Results: 88 and 41 DEGs were identified for LV and RV tissues between HLHS and controls, respectively. DEGs in LV tissues of HLHS were distinctly involved in heart development, apoptotic signaling pathway and ECM receptor interaction. DEGs in RV tissues of HLHS were mainly enriched in BMP signaling pathway, regulation of cell development and regulation of blood pressure. A total of 16 co-expression network were constructed. Among them, black module (r=0.79 and p-value=2e-04) and pink module (r=0.84 and p-value=4e-05) had the most significant correlation with HLHS, indicating that the two modules could be the most relevant for HLHS progression. We identified five hub genes in the black module (including Fbn1, Itga8, Itga11, Itgb5 and Thbs2), and five hub genes (including Cblb, Ccl2, Edn1, Itgb3 and Map2k1) in the pink module for HLHS. Their abnormal expression was verified in the GSE23959 dataset. Conclusion: Our findings revealed hub genes and key pathways for HLHS through WGCNA, which could play key roles in the molecular mechanism of HLHS.

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“…Недавние исследования показали, что интронный вариант, расположенный в гене регулятора 1 фосфатазы и актина -PHACTR1, влияет на транскрипционную активность гена эндотелина-1 (EDN1), расположенного на хромосоме 6. Известно, что ген PHACTR1 участвует в развитии гипертрофии стенок артерий, диссекции сонной артерии, ишемической болезни сердца и мигрени [17,18]. Дальнейшие генетические исследования будут способствовать улучшению понимания патофизиологических изменений при ФМД коронарных артерий.…”

Section: генетические и этиологические факторыunclassified

Modern Concepts of Fibromuscular Dysplasia of the Coronary Arteries

Трисветова

2019

Racionalʹnaâ farmakoterapiâ v kardiologii

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Fibromuscular dysplasia of the coronary arteries is a rare non-atherosclerotic and non-inflammatory vascular lesion that is asymptomatic until serious complications develop: stenosis, dissection, rupture, sudden cardiac death. Since there are no long-term numerous clinical observations of patients with fibromuscular dysplasia of the coronary arteries, recommendations have not been developed for diagnosing and treating the disease, which often manifests with acute coronary syndrome. In 2014, the European Consensus was published, and in 2019, the first international consensus document on the diagnosis and treatment of fibromuscular dysplasia with lesions of vessels from different regions (renal, cerebrovascular, coronary, and others). The documents state that the development of fibromuscular dysplasia of the coronary arteries considers the participation of the PHACTR1 gene mutation and the transcriptional activity of the EDN1 gene, smoking, prolonged exertion of the vascular wall, and possibly female sex hormones. In the case of acute coronary syndrome, the most informative diagnostic method is computed tomography with angiography, which reveals a smooth narrowing of the lumen in the middle or distal section in the epicardial artery, often due to intramural hematoma, and also finds dissection, spasm, and tortuous vessel. Additional diagnostic methods ‒ intravascular ultrasound and optical coherence tomography allow differentiation of fibromuscular dysplasia with atherosclerosis of the coronary artery, vasculitis, and other diseases. The choice of treatment tactics for fibromuscular dysplasia of the coronary arteries depends on the severity of the clinical manifestations ‒ conservative medical treatment and interventional methods are used.

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Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

Cited by 159 publications

References 46 publications

Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

Exploration and Validation of Hub Genes and Pathways in the Progression of Hypoplastic Left Heart Syndrome via Weighted Gene Co-Expression Network Analysis

Modern Concepts of Fibromuscular Dysplasia of the Coronary Arteries

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