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Alexander MR, Edwards TL, Harrison DG. GWAS for Defining the Pathogenesis of Hypertension: Have They Delivered? Hypertension 2025; 82:573-582. [PMID: 39936322 PMCID: PMC11922662 DOI: 10.1161/hypertensionaha.124.23451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025]
Abstract
Genome-wide association studies have identified >3500 associated single nucleotide polymorphisms and over 1000 independent loci associated with hypertension. These individually have small effect sizes, and few associated loci have been experimentally tested for causal roles in hypertension using animal models or in humans. Thus, methods to prioritize and maximize the relevance of identified single nucleotide polymorphisms and associated loci are critical to determine their importance in hypertension. We propose several approaches to aid in these efforts, including: (1) integration of genome-wide association study data with multiomic data sets, including proteomics, transcriptomics, and epigenomics, (2) utilizing linked clinical and genetic data sets to determine genetic contributions to hypertension subphenotypes with distinct drivers, and (3) performing whole exome/genome sequencing on cohorts of individuals with severe hypertension to enrich for rare variants with larger effect sizes. Rather than creating longer lists of hypertension-associated single nucleotide polymorphisms, these approaches are needed to identify key mediators of hypertension pathophysiology.
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Affiliation(s)
- Matthew R Alexander
- Department of Medicine, Division of Clinical Pharmacology (M.R.A., D.G.H.), Vanderbilt University Medical Center, Nashville, TN
- Division of Cardiovascular Medicine (M.R.A., D.G.H.), Vanderbilt University Medical Center, Nashville, TN
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN (M.R.A., D.G.H.)
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN (M.R.A., D.G.H.)
| | - Todd L Edwards
- Division of Epidemiology, Department of Medicine (T.L.E.), Vanderbilt University Medical Center, Nashville, TN
| | - David G Harrison
- Department of Medicine, Division of Clinical Pharmacology (M.R.A., D.G.H.), Vanderbilt University Medical Center, Nashville, TN
- Division of Cardiovascular Medicine (M.R.A., D.G.H.), Vanderbilt University Medical Center, Nashville, TN
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN (M.R.A., D.G.H.)
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN (M.R.A., D.G.H.)
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Doukhi D, Debette S, Mawet J. Headaches attributed to cranial and cervical artery dissections. J Headache Pain 2025; 26:28. [PMID: 39915731 PMCID: PMC11800537 DOI: 10.1186/s10194-025-01958-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/21/2025] [Indexed: 02/09/2025] Open
Abstract
Headache is a common neurological symptom, often leading to the investigation of secondary causes, including cerebrovascular conditions such as cranial and cervical artery dissection (CCAD). CCAD, a significant cause of stroke in younger adults, commonly presents with headache or neck pain, isolated or accompanied by neurological deficits, and may mimic primary headache disorders, complicating timely diagnosis. This review explores the role of headache in CCAD, specifically addressing headache as an initial presentation, its evolution post-dissection, and as a potential risk factor of CCAD. By synthesizing current evidence, the review aims to improve early detection and clinical management of CCAD in headache patients.
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Affiliation(s)
- Diana Doukhi
- Emergency Headache Center (Centre d'Urgences Céphalées), Department of Neurology, Lariboisière Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.
- FHU NeuroVasc, Paris, France.
- Université Paris Cité, Paris, France.
| | - Stéphanie Debette
- University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR1219, Bordeaux, F-33000, France
- Department of Neurology, Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, F-33000, France
| | - Jérome Mawet
- Emergency Headache Center (Centre d'Urgences Céphalées), Department of Neurology, Lariboisière Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France
- FHU NeuroVasc, Paris, France
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Lessard S, Chao M, Reis K, Beauvais M, Rajpal DK, Sloane J, Palta P, Klinger K, de Rinaldis E, Shameer K, Chatelain C. Leveraging large-scale multi-omics evidences to identify therapeutic targets from genome-wide association studies. BMC Genomics 2024; 25:1111. [PMID: 39563277 DOI: 10.1186/s12864-024-10971-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 10/28/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Therapeutic targets supported by genetic evidence from genome-wide association studies (GWAS) show higher probability of success in clinical trials. GWAS is a powerful approach to identify links between genetic variants and phenotypic variation; however, identifying the genes driving associations identified in GWAS remains challenging. Integration of molecular quantitative trait loci (molQTL) such as expression QTL (eQTL) using mendelian randomization (MR) and colocalization analyses can help with the identification of causal genes. Careful interpretation remains warranted because eQTL can affect the expression of multiple genes within the same locus. METHODS We used a combination of genomic features that include variant annotation, activity-by-contact maps, MR, and colocalization with molQTL to prioritize causal genes across 4,611 disease GWAS and meta-analyses from biobank studies, namely FinnGen, Estonian Biobank and UK Biobank. RESULTS Genes identified using this approach are enriched for gold standard causal genes and capture known biological links between disease genetics and biology. In addition, we find that eQTL colocalizing with GWAS are statistically enriched for corresponding disease-relevant tissues. We show that predicted directionality from MR is generally consistent with matched drug mechanism of actions (> 85% for approved drugs). Compared to the nearest gene mapping method, genes supported by multi-omics evidences displayed higher enrichment in approved therapeutic targets (risk ratio 1.75 vs. 2.58 for genes with the highest level of support). Finally, using this approach, we detected anassociation between the IL6 receptor signal transduction gene IL6ST and polymyalgia rheumatica, an indication for which sarilumab, a monoclonal antibody against IL-6, has been recently approved. CONCLUSIONS Combining variant annotation, activity-by-contact maps, and molQTL increases performance to identify causal genes, while informing on directionality which can be translated to successful target identification and drug development.
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Affiliation(s)
- Samuel Lessard
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | - Michael Chao
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | - Kadri Reis
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Mathieu Beauvais
- Digital R&D Data & Computational Sciences, Sanofi, Gentilly, France
| | - Deepak K Rajpal
- Translational Sciences, Sanofi, Framingham, MA, USA
- Pre-Clinical and Translational Sciences, Takeda, MA, USA
| | - Jennifer Sloane
- Immunology & Inflammation Development, Sanofi, Cambridge, MA, USA
| | - Priit Palta
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | | | | | - Khader Shameer
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | - Clément Chatelain
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA.
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4
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Takaoka M, Zhao X, Lim HY, Magnussen CG, Ang O, Suffee N, Schrank PR, Ong WS, Tsiantoulas D, Sommer F, Mohanta SK, Harrison J, Meng Y, Laurans L, Wu F, Lu Y, Masters L, Newland SA, Denti L, Hong M, Chajadine M, Juonala M, Koskinen JS, Kähönen M, Pahkala K, Rovio SP, Mykkänen J, Thomson R, Kaisho T, Habenicht AJR, Clement M, Tedgui A, Ait-Oufella H, Zhao TX, Nus M, Ruhrberg C, Taleb S, Williams JW, Raitakari OT, Angeli V, Mallat Z. Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis. Nature 2024; 634:457-465. [PMID: 39231480 PMCID: PMC11464399 DOI: 10.1038/s41586-024-07993-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 08/27/2024] [Indexed: 09/06/2024]
Abstract
Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2-4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.
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MESH Headings
- Adolescent
- Adult
- Animals
- Child
- Child, Preschool
- Female
- Humans
- Male
- Mice
- Middle Aged
- Young Adult
- Atherosclerosis/epidemiology
- Atherosclerosis/etiology
- Atherosclerosis/genetics
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Cholesterol, LDL/blood
- Cholesterol, LDL/metabolism
- Diet, Western/adverse effects
- Diet, Western/statistics & numerical data
- Finland/epidemiology
- Genome-Wide Association Study
- Hyperlipidemias/complications
- Hyperlipidemias/epidemiology
- Hyperlipidemias/genetics
- Hyperlipidemias/metabolism
- Hyperlipidemias/pathology
- Incidence
- Macrophages/metabolism
- Macrophages/pathology
- Mice, Inbred C57BL
- Phenotype
- Plaque, Atherosclerotic/epidemiology
- Plaque, Atherosclerotic/etiology
- Plaque, Atherosclerotic/genetics
- Plaque, Atherosclerotic/metabolism
- Plaque, Atherosclerotic/pathology
- Time Factors
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Affiliation(s)
- Minoru Takaoka
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Xiaohui Zhao
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Hwee Ying Lim
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Costan G Magnussen
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Owen Ang
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Nadine Suffee
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Patricia R Schrank
- Department of Integrative Biology & Physiology, Center for Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Wei Siong Ong
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Dimitrios Tsiantoulas
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Felix Sommer
- Institute of Clinical Molecular Biology, University of Kiel and University Hospital Schleswig Holstein (UKSH), Kiel, Germany
| | - Sarajo K Mohanta
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - James Harrison
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Yaxing Meng
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Ludivine Laurans
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Feitong Wu
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Yuning Lu
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Leanne Masters
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Stephen A Newland
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Laura Denti
- Institute of Ophthalmology, University College London, London, UK
| | - Mingyang Hong
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Mouna Chajadine
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Markus Juonala
- Department of Medicine, University of Turku, Turku, Finland
- Division of Medicine, Turku University Hospital, Turku, Finland
| | - Juhani S Koskinen
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Division of Medicine, Turku University Hospital, Turku, Finland
- Department of Medicine, Satakunta Central Hospital, Pori, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, University of Tampere, Tampere, Finland
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
- Finnish Cardiovascular Research Center Tampere, University of Tampere, Tampere, Finland
| | - Katja Pahkala
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Suvi P Rovio
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Juha Mykkänen
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Russell Thomson
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Analytical Edge, Hobart, Tasmania, Australia
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Andreas J R Habenicht
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Marc Clement
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Alain Tedgui
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Hafid Ait-Oufella
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Tian X Zhao
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Meritxell Nus
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | | | - Soraya Taleb
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Jesse W Williams
- Department of Integrative Biology & Physiology, Center for Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Olli T Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
| | - Véronique Angeli
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Ziad Mallat
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK.
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France.
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5
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Katz AE, Gupte T, Ganesh SK. From Atherosclerosis to Spontaneous Coronary Artery Dissection: Defining a Clinical and Genetic Risk Spectrum for Myocardial Infarction. Curr Atheroscler Rep 2024; 26:331-340. [PMID: 38761354 DOI: 10.1007/s11883-024-01208-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2024] [Indexed: 05/20/2024]
Abstract
PURPOSE OF REVIEW Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease. RECENT FINDINGS Recent studies have revealed several associated variants with varying effect sizes for SCAD, giving rise to a complex genetic architecture. Associated genes highlight an important role for arterial cells and their extracellular matrix in the pathogenesis of SCAD, as well as notable genetic overlap between SCAD and other systemic arteriopathies such as fibromuscular dysplasia and vascular connective tissue diseases. Further investigation of individual variants (including in the associated gene PHACTR1) along with polygenic score analysis have demonstrated an inverse genetic relationship between SCAD and atherosclerosis as distinct causes of AMI. SCAD represents an increasingly recognized cause of AMI with opposing clinical and genetic risk factors from that of AMI due to atherosclerosis, and it is often associated with complex underlying genetic conditions. Genetic study of SCAD on a larger scale and with more diverse cohorts will not only further our evolving understanding of a newly defined genetic spectrum for AMI, but it will also inform the clinical utility of integrating genetic testing in AMI prevention and management moving forward.
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Affiliation(s)
- Alexander E Katz
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Trisha Gupte
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Santhi K Ganesh
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
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Abstract
PURPOSE OF REVIEW Spontaneous coronary artery dissection (SCAD) is a significant cause of acute myocardial infarction that is increasingly recognized in young and middle-aged women. The etiology of SCAD is likely multifactorial and may include the interaction of environmental and individual factors. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD. RECENT FINDINGS The molecular findings underlying SCAD have been demonstrated to include a combination of rare DNA sequence variants with large effects, common variants contributing to a complex genetic architecture, and variants with intermediate impact. The genes associated with SCAD highlight the role of arterial cells and their extracellular matrix in the pathogenesis of the disease and shed light on the relationship between SCAD and other disorders, including fibromuscular dysplasia and connective tissue diseases. While up to 10% of affected individuals may harbor a rare variant with large effect, SCAD most often presents as a complex genetic condition. Analyses of larger and more diverse cohorts will continue to improve our understanding of risk susceptibility loci and will also enable consideration of the clinical utility of genetic testing strategies in the management of SCAD.
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Affiliation(s)
- Alexander E Katz
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, USA
- Department of Human Genetics, University of Michigan, 7220, MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-0644, USA
| | - Santhi K Ganesh
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, USA.
- Department of Human Genetics, University of Michigan, 7220, MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-0644, USA.
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Jiang D, Liu H, Zhu G, Li X, Fan L, Zhao F, Xu C, Wang S, Rose Y, Rhen J, Yu Z, Yin Y, Gu Y, Xu X, Fisher EA, Ge J, Xu Y, Pang J. Endothelial PHACTR1 Promotes Endothelial Activation and Atherosclerosis by Repressing PPARγ Activity Under Disturbed Flow in Mice. Arterioscler Thromb Vasc Biol 2023; 43:e303-e322. [PMID: 37199156 PMCID: PMC10524336 DOI: 10.1161/atvbaha.122.318173] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 05/02/2023] [Indexed: 05/19/2023]
Abstract
BACKGROUND Numerous genome-wide association studies revealed that SNPs (single nucleotide polymorphisms) at the PHACTR1 (phosphatase and actin regulator 1) locus strongly correlate with coronary artery disease. However, the biological function of PHACTR1 remains poorly understood. Here, we identified the proatherosclerotic effect of endothelial PHACTR1, contrary to macrophage PHACTR1. METHODS We generated global (Phactr1-/-) and endothelial cell (EC)-specific (Phactr1ECKO) Phactr1 KO (knockout) mice and crossed these mice with apolipoprotein E-deficient (Apoe-/-) mice. Atherosclerosis was induced by feeding the high-fat/high-cholesterol diet for 12 weeks or partially ligating carotid arteries combined with a 2-week high-fat/high-cholesterol diet. PHACTR1 localization was identified by immunostaining of overexpressed PHACTR1 in human umbilical vein ECs exposed to different types of flow. The molecular function of endothelial PHACTR1 was explored by RNA sequencing using EC-enriched mRNA from global or EC-specific Phactr1 KO mice. Endothelial activation was evaluated in human umbilical vein ECs transfected with siRNA targeting PHACTR1 and in Phactr1ECKO mice after partial carotid ligation. RESULTS Global or EC-specific Phactr1 deficiency significantly inhibited atherosclerosis in regions of disturbed flow. PHACTR1 was enriched in ECs and located in the nucleus of disturbed flow areas but shuttled to cytoplasm under laminar flow in vitro. RNA sequencing showed that endothelial Phactr1 depletion affected vascular function, and PPARγ (peroxisome proliferator-activated receptor gamma) was the top transcription factor regulating differentially expressed genes. PHACTR1 functioned as a PPARγ transcriptional corepressor by binding to PPARγ through the corepressor motifs. PPARγ activation protects against atherosclerosis by inhibiting endothelial activation. Consistently, PHACTR1 deficiency remarkably reduced endothelial activation induced by disturbed flow in vivo and in vitro. PPARγ antagonist GW9662 abolished the protective effects of Phactr1 KO on EC activation and atherosclerosis in vivo. CONCLUSIONS Our results identified endothelial PHACTR1 as a novel PPARγ corepressor to promote atherosclerosis in disturbed flow regions. Endothelial PHACTR1 is a potential therapeutic target for atherosclerosis treatment.
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Affiliation(s)
- Dongyang Jiang
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Hao Liu
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Guofu Zhu
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Xiankai Li
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Linlin Fan
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Faxue Zhao
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Chong Xu
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Shumin Wang
- Aab Cardiovascular Research Institute, Department of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA (S. W., Y. R., J. R., X. X., J. P.)
| | - Yara Rose
- Aab Cardiovascular Research Institute, Department of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA (S. W., Y. R., J. R., X. X., J. P.)
| | - Jordan Rhen
- Aab Cardiovascular Research Institute, Department of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA (S. W., Y. R., J. R., X. X., J. P.)
| | - Ze Yu
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Yiheng Yin
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Yuling Gu
- Shanghai Naturethink Life Science&Technology Co., Itd, Shanghai 201809, China (Y. G.)
| | - Xiangbin Xu
- Aab Cardiovascular Research Institute, Department of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA (S. W., Y. R., J. R., X. X., J. P.)
| | - Edward A. Fisher
- Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA (E. A. F.)
| | - Junbo Ge
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Yawei Xu
- Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China (D. J., H. L., G. Z., X. L., L. F., F. Z., C. X., Z. Y., Y. Y., J. G., Y. X.)
| | - Jinjiang Pang
- Aab Cardiovascular Research Institute, Department of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA (S. W., Y. R., J. R., X. X., J. P.)
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Rezvan A. PHACTR1 and Atherosclerosis: It's Complicated. Arterioscler Thromb Vasc Biol 2023; 43:1409-1411. [PMID: 37317846 PMCID: PMC10527601 DOI: 10.1161/atvbaha.123.319545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Affiliation(s)
- Amir Rezvan
- Division of Cardiology, Emory University School of Medicine, Atlanta, GA
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9
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Rada I, Calderón JF, Martínez G, Muñoz Venturelli P. Genetics of spontaneous cervical and coronary artery dissections. Front Glob Womens Health 2023; 4:1007795. [PMID: 37214559 PMCID: PMC10196206 DOI: 10.3389/fgwh.2023.1007795] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 04/14/2023] [Indexed: 05/24/2023] Open
Abstract
Objectives Spontaneous cervical artery dissections (SCeAD) and coronary artery dissections (SCoAD) are major causes of neurovascular and cardiovascular morbidity in young adults. Although multiple aspects of their etiology are still unknown, most consensuses are focused on the presence of constitutional genetic aspects and environmental triggers. Since recent evidence of genetic contribution points to a possible overlap between these conditions, we aimed to describe current information on SCeAD and SCoAD genetics and their potential shared pathological aspects. Materials and methods A narrative review is presented. Publications in English and Spanish were queried using database search. The articles were evaluated by one team member in terms of inclusion criteria. After collecting, the articles were categorized based on scientific content. Results Given that patients with SCeAD and SCoAD rarely present connective tissue disorders, other genetic loci are probably responsible for the increased susceptibility in some individuals. The common variant rs9349379 at PHACTR1 gene is associated with predisposition to pathologies of the arterial wall, likely mediated by variations in Endothelin-1 (ET-1) levels. The risk of arterial dissection may be increased for those who carry the rs9349379(A) allele, associated with lower expression levels of ET-1; however, the local effect of this vasomotor imbalance remains unclear. Sex differences seen in SCeAD and SCoAD support a role for sex hormones that could modulate risk, tilting the delicate balance and forcing vasodilator actions to prevail over vasoconstriction due to a reduction in ET-1 expression. Conclusions New evidence points to a common gene variation that could explain dissection in both the cervical and coronary vasculatures. To further confirm the risk conferred by the rs9349379 variant, genome wide association studies are warranted, hopefully in larger and ethnically diverse populations.
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Affiliation(s)
- Isabel Rada
- Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Juan Francisco Calderón
- Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Gonzalo Martínez
- División de Enfermedades Cardiovasculares, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Paula Muñoz Venturelli
- Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile
- The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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10
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Wood A, Antonopoulos A, Chuaiphichai S, Kyriakou T, Diaz R, Al Hussaini A, Marsh AM, Sian M, Meisuria M, McCann G, Rashbrook VS, Drydale E, Draycott S, Polkinghorne MD, Akoumianakis I, Antoniades C, Watkins H, Channon KM, Adlam D, Douglas G. PHACTR1 modulates vascular compliance but not endothelial function: a translational study. Cardiovasc Res 2023; 119:599-610. [PMID: 35653516 PMCID: PMC10064844 DOI: 10.1093/cvr/cvac092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/09/2022] [Accepted: 05/19/2022] [Indexed: 11/13/2022] Open
Abstract
AIMS The non-coding locus at 6p24 located in Intron 3 of PHACTR1 has consistently been implicated as a risk allele in myocardial infarction and multiple other vascular diseases. Recent murine studies have identified a role for Phactr1 in the development of atherosclerosis. However, the role of PHACTR1 in vascular tone and in vivo vascular remodelling has yet to be established. The aim of this study was to investigate the role of PHACTR1 in vascular function. METHODS AND RESULTS Prospectively recruited coronary artery disease (CAD) patients undergoing bypass surgery and retrospectively recruited spontaneous coronary artery dissection (SCAD) patients and matched healthy volunteers were genotyped at the PHACTR1 rs9349379 locus. We observed a significant association between the PHACTR1 loci and changes in distensibility in both the ascending aorta (AA = 0.0053 ± 0.0004, AG = 0.0041 ± 0.003, GG = 0.0034 ± 0.0009, P < 0.05, n = 58, 54, and 7, respectively) and carotid artery (AA = 12.83 ± 0.51, AG = 11.14 ± 0.38, GG = 11.69 ± 0.66, P < 0.05, n = 70, 65, and 18, respectively). This association was not observed in the descending aorta or in SCAD patients. In contrast, the PHACTR1 locus was not associated with changes in endothelial cell function with no association between the rs9349379 locus and in vivo or ex vivo vascular function observed in CAD patients. This finding was confirmed in our murine model where the loss of Phactr1 on the pro-atherosclerosis ApoE-/- background did not alter ex vivo vascular function. CONCLUSION In conclusion, we have shown a role for PHACTR1 in arterial compliance across multiple vascular beds. Our study suggests that PHACTR1 has a key structural role within the vasculature.
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Affiliation(s)
- Alice Wood
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Alexios Antonopoulos
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Surawee Chuaiphichai
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Theodosios Kyriakou
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Rebeca Diaz
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Abtehale Al Hussaini
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Anna-Marie Marsh
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Manjit Sian
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Mitul Meisuria
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Gerry McCann
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Victoria S Rashbrook
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Edward Drydale
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Sally Draycott
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Murray David Polkinghorne
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Ioannis Akoumianakis
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Charalambos Antoniades
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Hugh Watkins
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Keith M Channon
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
| | - David Adlam
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Gillian Douglas
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
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11
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Peña-Martínez EG, Rivera-Madera A, Pomales-Matos DA, Sanabria-Alberto L, Rosario-Cañuelas BM, Rodríguez-Ríos JM, Carrasquillo-Dones EA, Rodríguez-Martínez JA. Disease-associated non-coding variants alter NKX2-5 DNA-binding affinity. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194906. [PMID: 36690178 PMCID: PMC10013089 DOI: 10.1016/j.bbagrm.2023.194906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/30/2022] [Accepted: 01/02/2023] [Indexed: 01/22/2023]
Abstract
Genome-wide association studies (GWAS) have mapped over 90 % of disease- or trait-associated variants within the non-coding genome, like cis-regulatory elements (CREs). Non-coding single nucleotide polymorphisms (SNPs) are genomic variants that can change how DNA-binding regulatory proteins, like transcription factors (TFs), interact with the genome and regulate gene expression. NKX2-5 is a TF essential for proper heart development, and mutations affecting its function have been associated with congenital heart diseases (CHDs). However, establishing a causal mechanism between non-coding genomic variants and human disease remains challenging. To address this challenge, we identified 8475 SNPs predicted to alter NKX2-5 DNA-binding using a position weight matrix (PWM)-based predictive model. Five variants were prioritized for in vitro validation; four of them are associated with traits and diseases that impact cardiovascular health. The impact of these variants on NKX2-5 binding was evaluated with electrophoretic mobility shift assay (EMSA) using purified recombinant NKX2-5 homeodomain. Binding curves were constructed to determine changes in binding between variant and reference alleles. Variants rs7350789, rs7719885, rs747334, and rs3892630 increased binding affinity, whereas rs61216514 decreased binding by NKX2-5 when compared to the reference genome. Our findings suggest that differential TF-DNA binding affinity can be key in establishing a causal mechanism of pathogenic variants.
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12
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Ma X, Su M, He Q, Zhang Z, Zhang F, Liu Z, Sun L, Weng J, Xu S. PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction. Front Immunol 2022; 13:958677. [PMID: 36091033 PMCID: PMC9457086 DOI: 10.3389/fimmu.2022.958677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/01/2022] [Indexed: 01/13/2023] Open
Abstract
Genome-wide association studies (GWAS) have recently identified phosphatase and actin regulator-1 (PHACTR1) as a critical risk gene associated with polyvascular diseases. However, it remains largely unclear how PHACTR1 is involved in endothelial dysfunction. Here, by mining published datasets of human stable and vulnerable/ruptured plaque tissues, we observed upregulated expression of PHACTR1 in vulnerable/ruptured plaques. Congruent with these data, we demonstrated increased Phactr1 gene expression in aortic endothelium from ApoE-/- mice fed a western type diet compared with that in normal C57BL/6J mice. Relevantly, PHACTR1 gene expression was upregulated by pro-inflammatory and pro-atherogenic stimuli, including TNF-α, IL-1β and oxidized LDL (oxLDL). By employing next-generation RNA sequencing, we demonstrate that PHACTR1 overexpression disrupts pathways associated with endothelial homeostasis. Cell biological studies unravel that PHACTR1 mediates endothelial inflammation and monocyte adhesion by activating NF-κB dependent intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) expression. In addition, overexpression of PHACTR1 also reduces the generation of nitric oxide (NO) by inhibiting Akt/eNOS activation. In-house compound screening of vasoprotective drugs identifies several drugs, including lipid-lowering statins, decreases PHACTR1 gene expression. However, PHACTR1 gene expression was not affected by another lipid-lowering drug-fenofibrate. We also performed a proteomic study to reveal PHACTR1 interacting proteins and validated that PHACTR1 can interact with heat shock protein A8 (HSPA8) which was reported to be associated with coronary artery disease and eNOS degradation. Further studies are warranted to confirm the precise mechanism of PHACTR1 in driving endothelial dysfunction. In conclusion, by using systems biology approach and molecular validation, we disclose the deleterious effects of PHACTR1 on endothelial function by inducing endothelial inflammation and reducing NO production, highlighting the potential to prevent endothelial dysfunction and atherosclerosis by targeting PHACTR1 expression. The precise role of endothelial cell PHACTR1 in polyvascular diseases remains to be validated in diseased conditions.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Suowen Xu
- *Correspondence: Suowen Xu, ; Jianping Weng,
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13
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Francis CM, Futschik ME, Huang J, Bai W, Sargurupremraj M, Teumer A, Breteler MMB, Petretto E, Ho ASR, Amouyel P, Engelter ST, Bülow R, Völker U, Völzke H, Dörr M, Imtiaz MA, Aziz NA, Lohner V, Ware JS, Debette S, Elliott P, Dehghan A, Matthews PM. Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities. Nat Commun 2022; 13:4505. [PMID: 35922433 PMCID: PMC9349177 DOI: 10.1038/s41467-022-32219-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 07/20/2022] [Indexed: 12/13/2022] Open
Abstract
Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
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Affiliation(s)
- Catherine M Francis
- National Heart and Lung Institute, Imperial College London, Programme in Cardiovascular Genetics and Genomics, London, UK
- Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, SW3 6NP, UK
| | - Matthias E Futschik
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- MRC London Institute of Medical Sciences (LMS), Imperial College London, London, W12 0NN, UK
| | - Jian Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Wenjia Bai
- Department of Brain Sciences, Imperial College London, London, UK
- Department of Computing, Imperial College London, London, UK
| | - Muralidharan Sargurupremraj
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, 78229, USA
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, 33000, Bordeaux, France
| | - Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
| | - Monique M B Breteler
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany
| | - Enrico Petretto
- Programme in Cardiovascular & Metabolic Disorders and Centre for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore
- Institute of Big Data and Artificial Intelligence, China Pharmaceutical University (CPU), 211198, Nanjing, China
- Computational Biology Programme, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Amanda S R Ho
- Computational Biology Programme, Faculty of Science, National University of Singapore, Singapore, Singapore
| | - Philippe Amouyel
- LabEx DISTALZ-U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille, Lille, France
- Inserm, U1167, Lille, France
- Centre Hospitalier Universitaire Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Stefan T Engelter
- Department of Neurology and Stroke Center, University Hospital and University of Basel, Petersgraben 4, CH - 4031, Basel, Switzerland
- Department of Clinical Neurology and Neurorehabilitation, University Department of Geriatric Medicine FELIX PLATTER, University of Basel, Basel, Switzerland
| | - Robin Bülow
- Department of Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
| | - Uwe Völker
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
| | - Marcus Dörr
- DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
| | - Mohammed-Aslam Imtiaz
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - N Ahmad Aziz
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department of Neurology, Faculty of Medicine, University of Bonn, Bonn, Germany
| | - Valerie Lohner
- Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - James S Ware
- National Heart and Lung Institute, Imperial College London, Programme in Cardiovascular Genetics and Genomics, London, UK
- Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, SW3 6NP, UK
- MRC London Institute of Medical Sciences (LMS), Imperial College London, London, W12 0NN, UK
| | - Stephanie Debette
- University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, 33000, Bordeaux, France
- Department of Neurology, Institute for Neurodegenerative Diseases, Bordeaux University Hospital - CHU Bordeaux, 33000, Bordeaux, France
| | - Paul Elliott
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- UK Dementia Research Institute at Imperial College London, London, UK
- Health Data Research (HDR) UK London at Imperial College London, London, UK
- Britsh Heart Foundation Centre of Research Excellence at Imperial College London, London, UK
- National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London, London, UK
- MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
| | - Abbas Dehghan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
- UK Dementia Research Institute at Imperial College London, London, UK.
| | - Paul M Matthews
- Department of Brain Sciences, Imperial College London, London, UK.
- UK Dementia Research Institute at Imperial College London, London, UK.
- National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London, London, UK.
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14
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Turner AW, Hu SS, Mosquera JV, Ma WF, Hodonsky CJ, Wong D, Auguste G, Song Y, Sol-Church K, Farber E, Kundu S, Kundaje A, Lopez NG, Ma L, Ghosh SKB, Onengut-Gumuscu S, Ashley EA, Quertermous T, Finn AV, Leeper NJ, Kovacic JC, Björkegren JLM, Zang C, Miller CL. Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk. Nat Genet 2022; 54:804-816. [PMID: 35590109 PMCID: PMC9203933 DOI: 10.1038/s41588-022-01069-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 03/31/2022] [Indexed: 12/24/2022]
Abstract
Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell-type-specific elements and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single-nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk.
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Affiliation(s)
- Adam W Turner
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Shengen Shawn Hu
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jose Verdezoto Mosquera
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
| | - Wei Feng Ma
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Medical Scientist Training Program, University of Virginia, Charlottesville, VA, USA
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Chani J Hodonsky
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
| | - Doris Wong
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
| | - Gaëlle Auguste
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Yipei Song
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Katia Sol-Church
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
- Genome Analysis & Technology Core, University of Virginia, Charlottesville, VA, USA
| | - Emily Farber
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Genome Sciences Laboratory, University of Virginia, Charlottesville, VA, USA
| | - Soumya Kundu
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Anshul Kundaje
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | - Nicolas G Lopez
- Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, CA, USA
| | - Lijiang Ma
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Suna Onengut-Gumuscu
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Genome Sciences Laboratory, University of Virginia, Charlottesville, VA, USA
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Euan A Ashley
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Thomas Quertermous
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA
| | | | - Nicholas J Leeper
- Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, CA, USA
| | - Jason C Kovacic
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
- St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Johan L M Björkegren
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Chongzhi Zang
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
| | - Clint L Miller
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
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15
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Rubin S, Bougaran P, Martin S, Abelanet A, Delobel V, Pernot M, Jeanningros S, Bats ML, Combe C, Dufourcq P, Debette S, Couffinhal T, Duplàa C. PHACTR-1 (Phosphatase and Actin Regulator 1) Deficiency in Either Endothelial or Smooth Muscle Cells Does Not Predispose Mice to Nonatherosclerotic Arteriopathies in 3 Transgenic Mice. Arterioscler Thromb Vasc Biol 2022; 42:597-609. [PMID: 35387477 DOI: 10.1161/atvbaha.122.317431] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Genome-wide association studies have revealed robust associations of common genetic polymorphisms in an intron of the PHACTR-1 (phosphatase and actin regulator 1) gene (chr6p24), with cervical artery dissection, spontaneous coronary artery dissection, and fibromuscular dysplasia. The aim was to assess its role in the pathogenesis of cervical artery dissection or fibromuscular dysplasia. METHODS Using various tissue-specific Cre-driver mouse lines, Phactr1 was deleted either in endothelial cells using 2 tissue-specific Cre-driver (PDGFB [platelet-derived growth factor B]-CreERT2 mice and Tie2 [tyrosine kinase with immunoglobulin and EGF homology domains]-Cre) and smooth muscle cells (smooth muscle actin-CreERT2) with a third tissue-specific Cre-driver. RESULTS To test the efficacy of the Phactr1 deletion after cre-induction, we confirmed first, a decrease in Phactr1 transcription and Phactr1 expression in endothelial cell and smooth muscle cell isolated from Phactr1iPDGFB and Phactr1iSMA mice. Irrespective to the tissue or the duration of the deletion, mice did not spontaneously display pathological phenotype or vascular impairment: mouse survival, growth, blood pressure, large vessel morphology, or actin organization were not different in knockout mice than their comparatives littermates. Challenging vascular function and repair either by angiotensin II-induced hypertension or limb ischemia did not lead to vascular morphology or function impairment in Phactr1-deleted mice. Similarly, there were no more consequences of Phactr1 deletion during embryogenesis in endothelial cells. CONCLUSIONS Loss of PHACTR-1 function in the cells involved in vascular physiology does not appear to induce a pathological vascular phenotype. The in vivo effect of the intronic variation described in genome-wide association studies is unlikely to involve downregulation in PHACTR-1 expression.
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Affiliation(s)
- Sébastien Rubin
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.).,Service de Néphrologie, Transplantation, Dialyse et Aphérèses (S.R., C.C.), Hôpital Pellegrin, CHU de Bordeaux, France
| | - Pauline Bougaran
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
| | - Soizic Martin
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
| | - Alice Abelanet
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
| | - Valentin Delobel
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
| | - Mathieu Pernot
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
| | - Sylvie Jeanningros
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
| | - Marie-Lise Bats
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.).,Service de Biochimie (M.-L.B.), Hôpital Pellegrin, CHU de Bordeaux, France
| | - Christian Combe
- Service de Néphrologie, Transplantation, Dialyse et Aphérèses (S.R., C.C.), Hôpital Pellegrin, CHU de Bordeaux, France.,University of Bordeaux, Unité INSERM 1026, Université de Bordeaux, France (C.C.)
| | - Pascale Dufourcq
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
| | - Stéphanie Debette
- University of Bordeaux, INSERM, Bordeaux Population Health Center, UMR1219, France (S.D.).,Bordeaux University Hospital, Department of Neurology, Institute of Neurodegenerative Diseases, France (S.D.)
| | - Thierry Couffinhal
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.).,Service des Maladies Cardiaques et Vasculaires, Hôpital Haut-Léveque CHU de Bordeaux, Pessac, France (T.C.)
| | - Cécile Duplàa
- University of Bordeaux, INSERM, Biologie des Maladies Cardiovasculaires, U1034, Pessac, France (S.R., P.B., S.M., A.A., V.D., M.P., S.J., M.-L.B., P.D., T.C., C.D.)
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16
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Alsheikh AJ, Wollenhaupt S, King EA, Reeb J, Ghosh S, Stolzenburg LR, Tamim S, Lazar J, Davis JW, Jacob HJ. The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases. BMC Med Genomics 2022; 15:74. [PMID: 35365203 PMCID: PMC8973751 DOI: 10.1186/s12920-022-01216-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 03/17/2022] [Indexed: 02/08/2023] Open
Abstract
Background The remarkable growth of genome-wide association studies (GWAS) has created a critical need to experimentally validate the disease-associated variants, 90% of which involve non-coding variants. Methods To determine how the field is addressing this urgent need, we performed a comprehensive literature review identifying 36,676 articles. These were reduced to 1454 articles through a set of filters using natural language processing and ontology-based text-mining. This was followed by manual curation and cross-referencing against the GWAS catalog, yielding a final set of 286 articles. Results We identified 309 experimentally validated non-coding GWAS variants, regulating 252 genes across 130 human disease traits. These variants covered a variety of regulatory mechanisms. Interestingly, 70% (215/309) acted through cis-regulatory elements, with the remaining through promoters (22%, 70/309) or non-coding RNAs (8%, 24/309). Several validation approaches were utilized in these studies, including gene expression (n = 272), transcription factor binding (n = 175), reporter assays (n = 171), in vivo models (n = 104), genome editing (n = 96) and chromatin interaction (n = 33). Conclusions This review of the literature is the first to systematically evaluate the status and the landscape of experimentation being used to validate non-coding GWAS-identified variants. Our results clearly underscore the multifaceted approach needed for experimental validation, have practical implications on variant prioritization and considerations of target gene nomination. While the field has a long way to go to validate the thousands of GWAS associations, we show that progress is being made and provide exemplars of validation studies covering a wide variety of mechanisms, target genes, and disease areas. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01216-w.
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Affiliation(s)
- Ammar J Alsheikh
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA.
| | - Sabrina Wollenhaupt
- Information Research, AbbVie Deutschland GmbH & Co. KG, 67061, Knollstrasse, Ludwigshafen, Germany
| | - Emily A King
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - Jonas Reeb
- Information Research, AbbVie Deutschland GmbH & Co. KG, 67061, Knollstrasse, Ludwigshafen, Germany
| | - Sujana Ghosh
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | | | - Saleh Tamim
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - Jozef Lazar
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - J Wade Davis
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
| | - Howard J Jacob
- Genomics Research Center, AbbVie Inc, North Chicago, Illinois, 60064, USA
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17
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Genetic Polymorphism of Matrix Metalloproteinase-9 and Susceptibility to Myocardial Infarction: A Meta-Analysis. DISEASE MARKERS 2022; 2022:5507153. [PMID: 35075377 PMCID: PMC8783703 DOI: 10.1155/2022/5507153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/10/2021] [Indexed: 12/01/2022]
Abstract
Objective Current findings on the association between MMP-9 rs3918242 and susceptibility to myocardial infarction (MI) are inconsistent, and their definite relationship is discussed in this meta-analysis. Methods Eligible literatures reporting MMP-9 rs3918242 and susceptibility to MI were searched in PubMed, Cochrane Library, CNRI, and VIP using keywords such as “MMP-9”, “matrix metallopeptidase-9” and “myocardial infarction”, “acute myocardial infarction”, “AMI”, and “polymorphism”. Data from eligible literatures were extracted for calculating OR and corresponding 95% CI using RevMan 5.3 and STATA12.0. Results Ten independent literatures reporting MMP-9 rs3918242 and susceptibility to MI were enrolled. Compared with subjects carrying CT&TT genotype of MMP-9 rs3918242, susceptibility to MI was lower in those carrying CC genotype (OR = 1.49, 95%CI = 1.19–1.86, P = 0.0004). Such a significance was observed in the overdominant (OR = 1.27, 95%CI = 1.14–1.41, P < 0.0001) and allele genetic models (OR = 1.43, 95%CI = 1.17–1.74, P = 0.0005) as well. This finding was also valid in the Asian population. Conclusions Mutation on MMP-9 rs3918242 has a potential relevance with susceptibility to MI.
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18
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Kosiński K, Malinowski D, Safranow K, Dziedziejko V, Pawlik A. PECAM1, COL4A2, PHACTR1, and LMOD1 Gene Polymorphisms in Patients with Unstable Angina. J Clin Med 2022; 11:jcm11020373. [PMID: 35054067 PMCID: PMC8778316 DOI: 10.3390/jcm11020373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 11/16/2022] Open
Abstract
Coronary artery disease (CAD) is a syndrome resulting from myocardial ischaemia of heterogeneous pathomechanism. Environmental and genetic factors contribute to its development. Atherosclerotic plaques that significantly narrow the lumen of coronary arteries cause symptoms of myocardial ischaemia. Acute coronary incidents are most often associated with plaque rupture or erosion accompanied by local activation of the coagulation system with thrombus formation. Plaque formation and stability are influenced by endothelial function and vascular smooth muscle cell function. In this study, we investigated the association between polymorphisms in genes affecting endothelial and vascular smooth muscle cell (VSMC) function and the occurrence of unstable angina pectoris. The aim of this study was to evaluate the association between the PECAM1 (rs1867624), COL4A2 (rs4773144), PHACTR1 (rs9349379) and LMOD1 (rs2820315) gene polymorphisms and the risk of unstable angina. The study included 232 patients with unstable angina diagnosed on the basis of clinical symptoms and coronary angiography and 144 healthy subjects with no significant coronary lumen stenosis at coronary angiography. There were no statistically significant differences in the distribution of COL4A2 rs4773144 and PECAM1 rs1867624 gene polymorphisms between patients with unstable angina and control subjects. In patients with unstable angina, there was an increased frequency of PHACTR1 rs9349379 G allele carriers (GG and AG genotypes) (GG+AG vs. AA, OR 1.71; 95% CI 1.10-2.66, p = 0.017) and carriers of the LMOD1 rs2820315 T allele (TT and CT genotypes) (TT+CT vs. CC, OR 1.65; 95% CI 1.09-2.51, p = 0.019) compared to the control group. The association between these alleles and unstable angina was confirmed by multivariate logistic regression analysis, in which the number of G (PHACTR1 rs9349379) and T (LMOD1 rs2820315) alleles was an independent risk factor for unstable angina. The results suggest an association between PHACTR1 rs9349379 and LMOD1 rs2820315 polymorphisms and the risk of unstable angina.
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Affiliation(s)
- Krzysztof Kosiński
- Department of Cardiology, Hospital in Szczecin, Arkonska 4, 71-455 Szczecin, Poland;
| | - Damian Malinowski
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.S.); (V.D.)
| | - Violetta Dziedziejko
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.S.); (V.D.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
- Correspondence:
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19
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Miyazawa K, Ito K. Genetic Analysis for Coronary Artery Disease Toward Diverse Populations. Front Genet 2021; 12:766485. [PMID: 34880905 PMCID: PMC8646044 DOI: 10.3389/fgene.2021.766485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/08/2021] [Indexed: 11/13/2022] Open
Abstract
Coronary artery disease is one of the leading causes of death in the world, and as such, it is one of the diseases for which genetic analyses have been actively conducted. In the early days, analyses of families with the aggregation of early-onset myocardial infarction, such as those with familial hypercholesterolemia, was the main focus, but since the practical application of genome-wide association study, the analysis of coronary artery disease as a common disease has progressed, and many disease-susceptibility loci have been identified. In addition, with the advancement of technologies, it has become possible to identify relatively rare genetic variants in a population-based analysis. These advances have not only revealed the detailed disease mechanisms but have also enabled the quantification of individual genetic risk and the development of new therapeutic agents. In this paper, some of those items, which are important to know in the current genetic analyses for coronary artery disease, are discussed.
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Affiliation(s)
- Kazuo Miyazawa
- Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kaoru Ito
- Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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20
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de Oliveira Campos JL, Bitencourt L, Pedrosa AL, Silva DF, Lin FJJ, de Oliveira Dias LT, Simões E Silva AC. Renovascular hypertension in pediatric patients: update on diagnosis and management. Pediatr Nephrol 2021; 36:3853-3868. [PMID: 33851262 DOI: 10.1007/s00467-021-05063-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/11/2021] [Accepted: 03/19/2021] [Indexed: 01/03/2023]
Abstract
Renovascular hypertension (RVH) is defined as an elevated blood pressure caused by kidney hypoperfusion, generally as a result of anatomic stenosis of the renal artery with consequent activation of the Renin Angiotensin-Aldosterone System. The main causes include genetic and inflammatory disorders, extrinsic compression, and idiopathic alterations. RVH is often asymptomatic and should be suspected in any child with refractory hypertension, especially if other suggestive findings are present, including those with severe hypertension, abdominal bruit, and abrupt fall of glomerular filtration rate after administration of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. There is a consensus that digital subtraction angiography is the gold standard method for the diagnosis of RVH. Nevertheless, the role of non-invasive imaging studies such as Doppler ultrasound, magnetic resonance angiography, or computed tomographic angiography remains controversial, especially due to limited pediatric evidence. The therapeutic approach should be individualized, and management options include non-surgical pharmacological therapy and revascularization with percutaneous transluminal renal angioplasty (PTRA) or surgery. The prognosis is related to the procedure performed, and PTRA has a higher restenosis rate compared to surgery, although a decreased risk of complications. This review summarizes the causes, physiopathology, diagnosis, treatment, and prognosis of RVH in pediatric patients. Further studies are required to define the best approach for RVH in children.
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Affiliation(s)
- Juliana Lacerda de Oliveira Campos
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Letícia Bitencourt
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Ana Luisa Pedrosa
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Diego Ferreira Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Filipe Ji Jen Lin
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Lucas Teixeira de Oliveira Dias
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
- Pediatric Nephrology Unit, Department of Pediatrics, Faculty of Medicine, UFMG, Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil.
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21
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Siew WS, Tang YQ, Kong CK, Goh BH, Zacchigna S, Dua K, Chellappan DK, Duangjai A, Saokaew S, Phisalprapa P, Yap WH. Harnessing the Potential of CRISPR/Cas in Atherosclerosis: Disease Modeling and Therapeutic Applications. Int J Mol Sci 2021; 22:8422. [PMID: 34445123 PMCID: PMC8395110 DOI: 10.3390/ijms22168422] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/27/2021] [Accepted: 08/02/2021] [Indexed: 12/26/2022] Open
Abstract
Atherosclerosis represents one of the major causes of death globally. The high mortality rates and limitations of current therapeutic modalities have urged researchers to explore potential alternative therapies. The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system is commonly deployed for investigating the genetic aspects of Atherosclerosis. Besides, advances in CRISPR/Cas system has led to extensive options for researchers to study the pathogenesis of this disease. The recent discovery of Cas9 variants, such as dCas9, Cas9n, and xCas9 have been established for various applications, including single base editing, regulation of gene expression, live-cell imaging, epigenetic modification, and genome landscaping. Meanwhile, other Cas proteins, such as Cas12 and Cas13, are gaining popularity for their applications in nucleic acid detection and single-base DNA/RNA modifications. To date, many studies have utilized the CRISPR/Cas9 system to generate disease models of atherosclerosis and identify potential molecular targets that are associated with atherosclerosis. These studies provided proof-of-concept evidence which have established the feasibility of implementing the CRISPR/Cas system in correcting disease-causing alleles. The CRISPR/Cas system holds great potential to be developed as a targeted treatment for patients who are suffering from atherosclerosis. This review highlights the advances in CRISPR/Cas systems and their applications in establishing pathogenetic and therapeutic role of specific genes in atherosclerosis.
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Affiliation(s)
- Wei Sheng Siew
- School of Biosciences, Taylor’s University, Subang Jaya 47500, Malaysia; (W.S.S.); (Y.Q.T.)
| | - Yin Quan Tang
- School of Biosciences, Taylor’s University, Subang Jaya 47500, Malaysia; (W.S.S.); (Y.Q.T.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences (FHMS), Taylor’s University, Subang Jaya 47500, Malaysia
| | - Chee Kei Kong
- Department of Primary Care Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Malaysia;
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
| | - Serena Zacchigna
- Centre for Translational Cardiology, Department of Medicine, Surgery and Health Sciences and Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, Strada di Fiume 447, 34149 Trieste, Italy;
- International Center for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia;
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University (IMU), Bukit Jalil 57000, Malaysia;
| | - Acharaporn Duangjai
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (A.D.); (S.S.)
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Surasak Saokaew
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (A.D.); (S.S.)
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Department of Pharmaceutical Care, Division of Pharmacy Practice, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Pochamana Phisalprapa
- Department of Medicine, Division of Ambulatory Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Wei Hsum Yap
- School of Biosciences, Taylor’s University, Subang Jaya 47500, Malaysia; (W.S.S.); (Y.Q.T.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences (FHMS), Taylor’s University, Subang Jaya 47500, Malaysia
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22
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Koitsopoulos PG, Rabkin SW. The association of polymorphism in PHACTR1 rs9349379 and rs12526453 with coronary artery atherosclerosis or coronary artery calcification. A systematic review. Coron Artery Dis 2021; 32:448-458. [PMID: 33660664 DOI: 10.1097/mca.0000000000000942] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE There is a need to identify genetic factors that may produce coronary artery atherosclerotic disease (CAD) that are not involved in the usual risk factors leading to CAD. Previous studies have often equated coronary artery calcification (CAC) with CAD with coronary stenosis or its sequelae. The objective of this study was to examine the relationship between phosphatase and actin regulator 1 (PHACTR1) single nucleotide polymorphisms (SNPs) and the type of coronary artery disease CAD versus CAC. METHOD A systematic review of the literature was conducted to answer the question of whether PHACTR1 gene polymorphisms are associated with coronary artery disease expressed as coronary artery atherosclerosis or CAC. RESULTS Eighteen studies spanning seven PHACTR1 SNPs were identified and evaluated for the relationship between PHACTR1 and coronary artery disease. There were significant relationships between rs9349379, rs12526453, and CAD with odds ratios (ORs) (confidence interval) of, respectively, 1.15 (1.13-1.17), 1.13 (1.09-1.17) but not for rs2026458, 1.03 (0.88-1.19). The OR for CAC was 1.22 (1.18-1.26) for rs9349379 and 1.28 (1.21-1.38) for rs12526453. CONCLUSIONS Several PHACTR1 specifically rs9349379 and rs12526453 polymorphisms but not rs2026458, are associated with CAD. There are differences in the association of PHACTR1 SNPs with CAC. PHACTR1 warrants more attention and study for the prevention and treatment of CAD.
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Affiliation(s)
| | - Simon W Rabkin
- Faculty of Medicine
- Department of Medicine (Cardiology), University of British Columbia, Vancouver, Canada
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23
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Kim ESH, Saw J, Kadian-Dodov D, Wood M, Ganesh SK. FMD and SCAD: Sex-Biased Arterial Diseases With Clinical and Genetic Pleiotropy. Circ Res 2021; 128:1958-1972. [PMID: 34110898 DOI: 10.1161/circresaha.121.318300] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.
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Affiliation(s)
- Esther S H Kim
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (E.S.H.K.)
| | - Jacqueline Saw
- Division of Cardiology, Vancouver General Hospital, University of British Columbia Canada (J.S.)
| | - Daniella Kadian-Dodov
- Zena and Michael A. Wiener Cardiovascular Institute, Marie-Joseé and Henry R. Kravis Center for Cardiovascular Health, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY (D.K.-D.)
| | - Malissa Wood
- Division of Cardiology, Harvard Medical School, Massachusetts General Hospital, Boston (M.W.)
| | - Santhi K Ganesh
- Division of Cardiovascular Medicine, Department of Internal Medicine (S.K.G.), University of Michigan Medical School, Ann Arbor.,Department of Human Genetics (S.K.G.), University of Michigan Medical School, Ann Arbor
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Yari A, Saleh-Gohari N, Mirzaee M, Hashemi F, Saeidi K. A Study of Associations Between rs9349379 (PHACTR1), rs2891168 (CDKN2B-AS), rs11838776 (COL4A2) and rs4880 (SOD2) Polymorphic Variants and Coronary Artery Disease in Iranian Population. Biochem Genet 2021; 60:106-126. [PMID: 34109516 DOI: 10.1007/s10528-021-10089-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/28/2021] [Indexed: 11/24/2022]
Abstract
Recent genome-wide association studies reported the association of polymorphic alleles of PHACTR1 (rs9349379 (G)), CDDKN2B-AS1 (rs2891168 (G)), COL4A2 (rs11838776 (A)) and SOD2 (rs4880 (T)) with increased risk of coronary artery disease (CAD). The aim of our study was to assess the association of genetic variants with risk of CAD and its severity and in Southeast Iranian population. This study was examined in 250 CAD-suspected patients (mean age 53.49 ± 6.9 years) and 250 healthy individuals (mean age 52.96 ± 5.9 years). The Taqman SNP genotyping assay was used for genotyping of rs9349379 and rs2891168 variants. Tetra-primer Amplified refractory mutation system-PCR (Tetra-primer ARMS-PCR) was employed for rs11838776 and rs4880. Multivariate logistic regression analyses indicated that the G allele of rs9349379 and rs2891168 were associated with increased risk of CAD. The GG homozygous genotype of rs9349379 and rs2891168 had also been associated with risk of CAD. Additionally, the AG genotype of rs2891168 was associated with CAD. The significance of association of rs2891168 (G, GG, AG) increases with severity of CAD; but the rs9349379 (G, GG) have shown reverse association with severity of CAD. The genetic variants of COL4A2 (rs11838776) and SOD2 (rs4880) reflected no association with CAD in Southeast Iranian population. The findings of this study revealed that the PHACTR1 (rs9349379) and CDKN2B-AS1 (rs2891168) genetic variants might serve as genetic risk factor in CAD.
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Affiliation(s)
- Abolfazl Yari
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.,Department of Medical Genetics, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Nasrollah Saleh-Gohari
- Department of Medical Genetics, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Moghaddameh Mirzaee
- Modeling in Health Research Center, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Fatemeh Hashemi
- Department of Medical Genetics, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.,Student Research Committee, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Kolsoum Saeidi
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran. .,Department of Medical Genetics, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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25
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Kasikara C, Schilperoort M, Gerlach B, Xue C, Wang X, Zheng Z, Kuriakose G, Dorweiler B, Zhang H, Fredman G, Saleheen D, Reilly MP, Tabas I. Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. J Clin Invest 2021; 131:145275. [PMID: 33630758 DOI: 10.1172/jci145275] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/23/2021] [Indexed: 12/14/2022] Open
Abstract
Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk allele to CAD via impaired efferocytosis. We show here that rs9349379-G/G was associated with lower levels of PHACTR1 and impaired efferocytosis in human monocyte-derived macrophages and human atherosclerotic lesional macrophages compared with rs9349379-A/A. Silencing PHACTR1 in human and mouse macrophages compromised AC engulfment, and Western diet-fed Ldlr-/- mice in which hematopoietic Phactr1 was genetically targeted showed impaired lesional efferocytosis, increased plaque necrosis, and thinner fibrous caps - all signs of vulnerable plaques in humans. Mechanistically, PHACTR1 prevented dephosphorylation of myosin light chain (MLC), which was necessary for AC engulfment. In summary, rs9349379-G lowered PHACTR1, which, by lowering phospho-MLC, compromised efferocytosis. Thus, rs9349379-G may contribute to CAD risk, at least in part, by impairing atherosclerotic lesional macrophage efferocytosis.
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Affiliation(s)
- Canan Kasikara
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Maaike Schilperoort
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Brennan Gerlach
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Chenyi Xue
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Xiaobo Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Ze Zheng
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - George Kuriakose
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | | | - Hanrui Zhang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Gabrielle Fredman
- Department of Molecular and Cellular Physiology, Albany Medical Center, Albany, New York, USA
| | - Danish Saleheen
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Muredach P Reilly
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Irving Institute for Clinical and Translational Research, Columbia University Irving Medical Center, New York, New York, USA
| | - Ira Tabas
- Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Department of Physiology and Cellular Biophysics and.,Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
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26
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Roberts R, Chang CC, Hadley T. Genetic Risk Stratification: A Paradigm Shift in Prevention of Coronary Artery Disease. ACTA ACUST UNITED AC 2021; 6:287-304. [PMID: 33778213 PMCID: PMC7987546 DOI: 10.1016/j.jacbts.2020.09.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/08/2020] [Accepted: 09/13/2020] [Indexed: 12/12/2022]
Abstract
CAD is a pandemic that can be prevented. Conventional risk factors are inadequate to detect who is at risk early in the asymptomatic stage. Genetic risk for CAD can be determined at birth, and those at highest genetic risk have been shown to respond to lifestyle changes and statin therapy with a 40% to 50% reduction in cardiac events. Genetic risk stratification for CAD should be brought to the bedside in an attempt to prevent this pandemic disease. Coronary artery disease (CAD) is a pandemic disease that is highly preventable as shown by secondary prevention. Primary prevention is preferred knowing that 50% of the population can expect a cardiac event in their lifetime. Risk stratification for primary prevention using the American Heart Association/American College of Cardiology predicted 10-year risk based on conventional risk factors for CAD is less than optimal. Conventional risk factors such as hypertension, cholesterol, and age are age-dependent and not present until the sixth or seventh decade of life. The genetic risk score (GRS), which is estimated from the recently discovered genetic variants predisposed to CAD, offers a potential solution to this dilemma. The GRS, which is derived from genotyping the population with a microarray containing these genetic risk variants, has indicated that genetic risk stratification based on the GRS is superior to that of conventional risk factors in detecting those at high risk and who would benefit most from statin therapy. Studies performed in >1 million individuals confirmed genetic risk stratification is superior and primarily independent of conventional risk factors. Prospective clinical trials based on risk stratification for CAD using the GRS have shown lifestyle changes, physical activity, and statin therapy are associated with 40% to 50% reduction in cardiac events in the high genetic risk group (20%). Genetic risk stratification has the advantage of being innate to an individual’s DNA, and because DNA does not change in a lifetime, it is independent of age. Genetic risk stratification is inexpensive and can be performed worldwide, providing risk analysis at any age and thus has the potential to revolutionize primary prevention.
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Key Words
- ACC, American College of Cardiology
- AHA, American Heart Association
- ANRIL, antisense non-coding RNA in the INK4 Locust
- CAD, coronary artery disease
- GRS, genetic risk score
- GWAS, genome-wide association study
- LDL-C, low-density lipoprotein cholesterol
- MR, Mendelian randomization
- SNP, single nucleotide polymorphism
- bp, base pair
- cardiovascular genetics
- coronary artery disease
- genetic risk score for CAD
- genome-wide association studies
- prevention of CAD
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Affiliation(s)
- Robert Roberts
- Department of Medicine, Dignity Health at St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
| | - Chih Chao Chang
- Department of Medicine, Dignity Health at St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
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Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease. Am J Hum Genet 2021; 108:411-430. [PMID: 33626337 DOI: 10.1016/j.ajhg.2021.02.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 02/04/2021] [Indexed: 02/08/2023] Open
Abstract
Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.
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Kuveljic J, Djuric T, Stankovic G, Dekleva M, Stankovic A, Alavantic D, Zivkovic M. Association of PHACTR1 intronic variants with the first myocardial infarction and their effect on PHACTR1 mRNA expression in PBMCs. Gene 2021; 775:145428. [PMID: 33460763 DOI: 10.1016/j.gene.2021.145428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/02/2020] [Accepted: 01/05/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Myocardial infarction (MI) and underlining atherosclerosis are the main causes of death worldwide. Phosphatase and actin regulator 1 (PHACTR1) variants have been associated with early onset MI, coronary artery disease and carotid dissection. PHACTR1 mRNA expression has been detected in tissues and cells related to atherosclerosis. Nonetheless, the true effect of PHACTR1 on vascular diseases is still unknown. Our aim was to examine the association of PHACTR1 intronic variants, rs9349379, rs2026458 and rs2876300, with MI and multi-vessel disease (MVD) and to assess their effect on PHACTR1 and EDN1 mRNA expression in PBMCs of patients six months after MI. METHODS The study enrolled 537 patients with the first MI and 310 controls. Gene expression was assessed in 74 patients six months after MI and 37 healthy controls. Rs9349379, rs2026458, rs2876300 and relative mRNA expressions were detected by TaqMan® technology. RESULTS The significant association between PHACTR1 variants and MI was not found, either individually or in haplotype. A higher frequency of rs2876300G-allele in MVD was rendered not significant after Bonferroni correction. PHACTR1 mRNA was significantly increased in PBMCs of patients six months after MI compared to controls (p = 0.02). Patients that carry ACG haplotype have increased PHACTR1 mRNA expression in PBMCs (p = 0.04). There was no effect of PHACTR1 variants on EDN1 mRNA expression. CONCLUSION Our findings suggest that PHACTR1 intronic variants may have a role in severity and progression of coronary atherosclerosis. Future research is needed to clarify the mechanism underlying the role of PHACTR1 in coronary atherosclerosis and MI.
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Affiliation(s)
- Jovana Kuveljic
- Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
| | - Tamara Djuric
- Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
| | - Goran Stankovic
- Cardiology Clinic, Clinical Center of Serbia, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milica Dekleva
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Department of Cardiology, University Clinical Center "Zvezdara", Belgrade, Serbia
| | - Aleksandra Stankovic
- Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
| | - Dragan Alavantic
- Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
| | - Maja Zivkovic
- Laboratory for Radiobiology and Molecular Genetics, "Vinca" Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
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29
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Varshney A, Chahal G, Santos L, Stolper J, Hallab JC, Nim HT, Nikolov M, Yip A, Ramialison M. Human Cardiac Transcription Factor Networks. SYSTEMS MEDICINE 2021. [DOI: 10.1016/b978-0-12-801238-3.11597-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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30
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Identification and Characterization of a Transcribed Distal Enhancer Involved in Cardiac Kcnh2 Regulation. Cell Rep 2020; 28:2704-2714.e5. [PMID: 31484079 DOI: 10.1016/j.celrep.2019.08.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 06/05/2019] [Accepted: 07/30/2019] [Indexed: 12/26/2022] Open
Abstract
The human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying IKr, a current critical for the repolarization phase of the cardiac action potential. Mutations in KCNH2 that cause a reduction of the repolarizing current can result in cardiac arrhythmias associated with long-QT syndrome. Here, we investigate the regulation of KCNH2 and identify multiple active enhancers. A transcribed enhancer ∼85 kbp downstream of Kcnh2 physically contacts the promoters of two Kcnh2 isoforms in a cardiac-specific manner in vivo. Knockdown of its ncRNA transcript results in reduced expression of Kcnh2b and two neighboring mRNAs, Nos3 and Abcb8, in vitro. Genomic deletion of the enhancer, including the ncRNA transcription start site, from the mouse genome causes a modest downregulation of both Kcnh2a and Kcnh2b in the ventricles. These findings establish that the regulation of Kcnh2a and Kcnh2b is governed by a complex regulatory landscape that involves multiple partially redundantly acting enhancers.
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31
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Turley TN, O'Byrne MM, Kosel ML, de Andrade M, Gulati R, Hayes SN, Tweet MS, Olson TM. Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection. JAMA Cardiol 2020; 5:929-938. [PMID: 32374345 DOI: 10.1001/jamacardio.2020.0872] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Importance Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. Objective To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. Design, Setting, and Participants This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. Main Outcomes and Measures Genetic loci and positional candidate genes associated with SCAD. Results This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). Conclusions and Relevance This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.
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Affiliation(s)
- Tamiel N Turley
- Molecular Pharmacology and Experimental Therapeutics Track, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota
| | - Megan M O'Byrne
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Matthew L Kosel
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Mariza de Andrade
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Rajiv Gulati
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Sharonne N Hayes
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Marysia S Tweet
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Timothy M Olson
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
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Villar D, Frost S, Deloukas P, Tinker A. The contribution of non-coding regulatory elements to cardiovascular disease. Open Biol 2020; 10:200088. [PMID: 32603637 PMCID: PMC7574544 DOI: 10.1098/rsob.200088] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/08/2020] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular disease collectively accounts for a quarter of deaths worldwide. Genome-wide association studies across a range of cardiovascular traits and pathologies have highlighted the prevalence of common non-coding genetic variants within candidate loci. Here, we review genetic, epigenomic and molecular approaches to investigate the contribution of non-coding regulatory elements in cardiovascular biology. We then discuss recent insights on the emerging role of non-coding variation in predisposition to cardiovascular disease, with a focus on novel mechanistic examples from functional genomics studies. Lastly, we consider the clinical significance of these findings at present, and some of the current challenges facing the field.
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Affiliation(s)
- Diego Villar
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
| | - Stephanie Frost
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
| | - Panos Deloukas
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Andrew Tinker
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
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Associations between PHACTR1 gene polymorphisms and pulse pressure in Chinese Han population. Biosci Rep 2020; 40:224380. [PMID: 32420588 PMCID: PMC7276519 DOI: 10.1042/bsr20193779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 05/12/2020] [Accepted: 05/15/2020] [Indexed: 11/25/2022] Open
Abstract
A genome-wide association study (GWAS) in Chinese twins was performed to explore associations between genes and pulse pressure (PP) in 2012, and detected a suggestive association in the phosphatase and actin regulator 1 (PHACTR1) gene on chromosome 6p24.1 (rs1223397, P=1.04e−07). The purpose of the present study was to investigate associations of PHACTR1 gene polymorphisms with PP in a Chinese population. We recruited 347 subjects with PP ≥ 65 mmHg as cases and 359 subjects with 30 ≤ PP ≤ 45 mmHg as controls. Seven single nucleotide polymorphisms (SNPs) in the PHACTR1 gene were genotyped. Logistic regression was performed to explore associations between SNPs and PP in codominant, additive, dominant, recessive and overdominant models. The Pearson’s χ2 test was applied to assess the relationships of haplotypes and PP. The A allele of rs9349379 had a positive effect on high PP. Multivariate logistic regression analysis showed that rs9349379 was significantly related to high PP in codominant [AA vs GG, 2.255 (1.132–4.492)], additive [GG vs GA vs AA, 1.368 (1.049–1.783)] and recessive [AA vs GA + GG, 2.062 (1.051–4.045)] models. The positive association between rs499818 and high PP was significant in codominant [AA vs GG, 3.483 (1.044–11.613)] and recessive [AA vs GG + GA, 3.716 (1.119–12.339)] models. No significant association of haplotypes with PP was detected. There was no significant interaction between six SNPs without strong linkage. In conclusion, the present study presents that rs9349379 and rs499818 in the PHACTR1 gene were significantly associated with PP in Chinese population. Future research should be conducted to confirm them.
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34
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Valenti MT, Serena M, Carbonare LD, Zipeto D. CRISPR/Cas system: An emerging technology in stem cell research. World J Stem Cells 2019; 11:937-956. [PMID: 31768221 PMCID: PMC6851009 DOI: 10.4252/wjsc.v11.i11.937] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 08/12/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
The identification of new and even more precise technologies for modifying and manipulating the genome has been a challenge since the discovery of the DNA double helix. The ability to modify selectively specific genes provides a powerful tool for characterizing gene functions, performing gene therapy, correcting specific genetic mutations, eradicating diseases, engineering cells and organisms to achieve new and different functions and obtaining transgenic animals as models for studying specific diseases. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology has recently revolutionized genome engineering. The application of this new technology to stem cell research allows disease models to be developed to explore new therapeutic tools. The possibility of translating new systems of molecular knowledge to clinical research is particularly appealing for addressing degenerative diseases. In this review, we describe several applications of CRISPR/Cas9 to stem cells related to degenerative diseases. In addition, we address the challenges and future perspectives regarding the use of CRISPR/Cas9 as an important technology in the medical sciences.
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Affiliation(s)
- Maria Teresa Valenti
- Department of Medicine, Section of Internal Medicine D, University of Verona, Verona 37134, Italy.
| | - Michela Serena
- Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
| | - Luca Dalle Carbonare
- Department of Medicine, Section of Internal Medicine D, University of Verona, Verona 37134, Italy
| | - Donato Zipeto
- Department of Neurosciences, Biomedicine and Movement Sciences, Laboratory of Molecular Biology, Verona 37134, Italy
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Adlam D, Olson TM, Combaret N, Kovacic JC, Iismaa SE, Al-Hussaini A, O'Byrne MM, Bouajila S, Georges A, Mishra K, Braund PS, d'Escamard V, Huang S, Margaritis M, Nelson CP, de Andrade M, Kadian-Dodov D, Welch CA, Mazurkiewicz S, Jeunemaitre X, Wong CMY, Giannoulatou E, Sweeting M, Muller D, Wood A, McGrath-Cadell L, Fatkin D, Dunwoodie SL, Harvey R, Holloway C, Empana JP, Jouven X, Olin JW, Gulati R, Tweet MS, Hayes SN, Samani NJ, Graham RM, Motreff P, Bouatia-Naji N. Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection. J Am Coll Cardiol 2019; 73:58-66. [PMID: 30621952 PMCID: PMC10403154 DOI: 10.1016/j.jacc.2018.09.085] [Citation(s) in RCA: 155] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 09/21/2018] [Accepted: 09/21/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES This study sought to test the association between the rs9349379 genotype and SCAD. METHODS Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
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Affiliation(s)
- David Adlam
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom.
| | - Timothy M Olson
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Nicolas Combaret
- Department of Cardiology, University Hospital of Clermont-Ferrand, Auvergne University, Clermont-Ferrand, France
| | - Jason C Kovacic
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine, Marie-Josée and Henry R. Kravis Cardiovascular Health Center at Mount Sinai, New York, New York
| | - Siiri E Iismaa
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Abtehale Al-Hussaini
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Megan M O'Byrne
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Sara Bouajila
- Department of Cardiology, University Hospital of Clermont-Ferrand, Auvergne University, Clermont-Ferrand, France
| | - Adrien Georges
- INSERM, Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, Paris-Descartes University, Sorbonne Paris Cité, Paris, France
| | - Ketan Mishra
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Peter S Braund
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Valentina d'Escamard
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine, Marie-Josée and Henry R. Kravis Cardiovascular Health Center at Mount Sinai, New York, New York
| | - Siying Huang
- INSERM, Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, Paris-Descartes University, Sorbonne Paris Cité, Paris, France
| | - Marios Margaritis
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Christopher P Nelson
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Mariza de Andrade
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Daniella Kadian-Dodov
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine, Marie-Josée and Henry R. Kravis Cardiovascular Health Center at Mount Sinai, New York, New York
| | - Catherine A Welch
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Stephani Mazurkiewicz
- INSERM, Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, Paris-Descartes University, Sorbonne Paris Cité, Paris, France
| | - Xavier Jeunemaitre
- INSERM, Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, Paris-Descartes University, Sorbonne Paris Cité, Paris, France; Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
| | - Claire Mei Yi Wong
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Eleni Giannoulatou
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Michael Sweeting
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - David Muller
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Alice Wood
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Lucy McGrath-Cadell
- St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Diane Fatkin
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Sally L Dunwoodie
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Richard Harvey
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Cameron Holloway
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Jean-Philippe Empana
- INSERM, Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, Paris-Descartes University, Sorbonne Paris Cité, Paris, France
| | - Xavier Jouven
- INSERM, Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, Paris-Descartes University, Sorbonne Paris Cité, Paris, France
| | - Jeffrey W Olin
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine, Marie-Josée and Henry R. Kravis Cardiovascular Health Center at Mount Sinai, New York, New York
| | - Rajiv Gulati
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Marysia S Tweet
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Sharonne N Hayes
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, and National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Robert M Graham
- Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia
| | - Pascal Motreff
- Department of Cardiology, University Hospital of Clermont-Ferrand, Auvergne University, Clermont-Ferrand, France
| | - Nabila Bouatia-Naji
- INSERM, Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, Paris-Descartes University, Sorbonne Paris Cité, Paris, France.
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Wang X, Musunuru K. Confirmation of Causal rs9349379- PHACTR1 Expression Quantitative Trait Locus in Human-Induced Pluripotent Stem Cell Endothelial Cells. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019; 11:e002327. [PMID: 30354304 DOI: 10.1161/circgen.118.002327] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Xiao Wang
- Division of Cardiology and Cardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
| | - Kiran Musunuru
- Division of Cardiology and Cardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
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Kuveljic J, Djuric T, Stankovic A, Koncar I, Alavantic D, Zivkovic M. PHACTR1 haplotypes are associated with carotid plaque presence and affect PHACTR1 mRNA expression in carotid plaque tissue. Gene 2019; 710:273-278. [DOI: 10.1016/j.gene.2019.06.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 04/25/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023]
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Lalonde S, Codina-Fauteux VA, de Bellefon SM, Leblanc F, Beaudoin M, Simon MM, Dali R, Kwan T, Lo KS, Pastinen T, Lettre G. Integrative analysis of vascular endothelial cell genomic features identifies AIDA as a coronary artery disease candidate gene. Genome Biol 2019; 20:133. [PMID: 31287004 PMCID: PMC6613242 DOI: 10.1186/s13059-019-1749-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 06/27/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene expression, open chromatin region, and 3D interactions in resting and TNFα-treated human endothelial cells. RESULTS We show that genetic variants associated with CAD and BP are enriched in open chromatin regions identified in endothelial cells. We identify physical loops by Hi-C and link open chromatin peaks that include CAD or BP SNPs with the promoters of genes expressed in endothelial cells. This analysis highlights 991 combinations of open chromatin regions and gene promoters that map to 38 CAD and 92 BP GWAS loci. We validate one CAD locus, by engineering a deletion of the TNFα-sensitive regulatory element using CRISPR/Cas9 and measure the effect on the expression of the novel CAD candidate gene AIDA. CONCLUSIONS Our data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD and hypertension.
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Affiliation(s)
- Simon Lalonde
- Montreal Heart Institute, 5000 Belanger street, Montréal, Québec H1T 1C8 Canada
| | - Valérie-Anne Codina-Fauteux
- Montreal Heart Institute, 5000 Belanger street, Montréal, Québec H1T 1C8 Canada
- Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4 Canada
| | - Sébastian Méric de Bellefon
- Montreal Heart Institute, 5000 Belanger street, Montréal, Québec H1T 1C8 Canada
- Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4 Canada
| | - Francis Leblanc
- Montreal Heart Institute, 5000 Belanger street, Montréal, Québec H1T 1C8 Canada
- Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4 Canada
| | - Mélissa Beaudoin
- Montreal Heart Institute, 5000 Belanger street, Montréal, Québec H1T 1C8 Canada
| | - Marie-Michelle Simon
- McGill University and Genome Québec Innovation Center, Montréal, Québec H3A 0G1 Canada
| | - Rola Dali
- McGill University and Genome Québec Innovation Center, Montréal, Québec H3A 0G1 Canada
| | - Tony Kwan
- McGill University and Genome Québec Innovation Center, Montréal, Québec H3A 0G1 Canada
| | - Ken Sin Lo
- Montreal Heart Institute, 5000 Belanger street, Montréal, Québec H1T 1C8 Canada
| | - Tomi Pastinen
- Center for Pediatric Genomic Medicine (CPGM), Children’s Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108 USA
| | - Guillaume Lettre
- Montreal Heart Institute, 5000 Belanger street, Montréal, Québec H1T 1C8 Canada
- Faculté de Médecine, Université de Montréal, Montréal, Québec H3T 1J4 Canada
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Abstract
Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly appreciated cause of acute myocardial infarction (AMI) and sudden cardiac death most often affecting young to middle-aged women with few conventional cardiovascular risk factors. Areas covered: A literature search was performed using MedLine, PubMed, and Google Scholar (dating to 04/30/2019). Authors review the key clinical features of SCAD and highlight what is known regarding its pathophysiology and associated factors. The relationship between SCAD and other systemic vasculopathies, notably fibromuscular dysplasia (FMD) is also discussed. Authors also mention the management of acute SCAD along with considerations for long term follow-up such as chest pain syndrome, extracoronary vasculopathy screening, and recurrent SCAD. Expert opinion: Our understanding regarding the association of SCAD and other arteriopathies such as FMD is anticipated to grow. In addition, progress is likely to be made in our efforts to predict recurrent SCAD risk and define potential preventative strategies, possibly through the incorporation of adjunctive imaging.
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Affiliation(s)
- Nicholas Y Tan
- a Department of Cardiovascular Diseases , Mayo Clinic , Rochester , MN , USA
| | - Marysia S Tweet
- a Department of Cardiovascular Diseases , Mayo Clinic , Rochester , MN , USA
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40
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Kovacic JC. Unraveling the Complex Genetics of Coronary Artery Disease. J Am Coll Cardiol 2019; 69:837-840. [PMID: 28209225 DOI: 10.1016/j.jacc.2016.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 12/04/2016] [Indexed: 10/20/2022]
Affiliation(s)
- Jason C Kovacic
- Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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41
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Genetics of Common, Complex Coronary Artery Disease. Cell 2019; 177:132-145. [DOI: 10.1016/j.cell.2019.02.015] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/11/2019] [Accepted: 02/11/2019] [Indexed: 01/08/2023]
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Chen L, Qian H, Luo Z, Li D, Xu H, Chen J, He P, Zhou X, Zhang T, Chen J, Min X. PHACTR1 gene polymorphism with the risk of coronary artery disease in Chinese Han population. Postgrad Med J 2019; 95:67-71. [PMID: 30777881 DOI: 10.1136/postgradmedj-2018-136298] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/16/2019] [Accepted: 01/20/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Coronary artery disease (CAD) is the most frequent multifactorial disease worldwide and is characterised by endothelial injury, lipid deposition and coronary artery calcification. The purpose of this study was to determine the allelic and genotypic frequencies of two loci (rs2026458 and rs9349379) of phosphatase and actin regulator 1 (PHACTR1) to the risk of developing CAD in the Chinese Han population. METHODS A case-control study was conducted including 332 patients with CAD and 119 controls. Genotype analysis was performed by PCR and Sanger sequencing. Genetic model analysis was performed to evaluate the association between single nucleotide polymorphisms and CAD susceptibility using Pearson's χ2 test and logistic regression analysis. RESULTS The GG genotype of rs9349379 represented 50% and 29% of patients with CAD and controls, respectively (p<0.001). The CC genotype of rs2026458 was more prevalent in the controls than in patients with CAD compared with TT genotype (OR=0.548, 95% CI 0.351 to 0.856, p=0.008). Logistic regression analyses revealed that PHACTR1 rs9349379 GG genotype was significantly associated with increased risk of CAD in the recessive model (OR=2.359, 95% CI 1.442 to 3.862, p=0.001), even after adjusting for age gender, hypertension, type 2 diabetes, hyperlipidaemia and smoking habit. Heterogeneity test proved that rs9349379's risk effects on CAD were more significant among women. CONCLUSIONS Our study indicate that the PHACTR1 rs9349379 polymorphism is associated with the increased risk for CAD in the female Chinese Han population.
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Affiliation(s)
- Lishan Chen
- Dongfeng Hospital Graduate Training Base, Jinzhou Medical University, Jinzhou, China.,Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Hang Qian
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Zhihuan Luo
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Dongfeng Li
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Hao Xu
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Jishun Chen
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Peigen He
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Xintao Zhou
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Tao Zhang
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Jun Chen
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
| | - Xinwen Min
- Department of Cardiology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, China
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Merkulov VM, Leberfarb EY, Merkulova TI. Regulatory SNPs and their widespread effects on the transcriptome. J Biosci 2018; 43:1069-1075. [PMID: 30541964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Currently, it is generally accepted that the cis-acting effects of noncoding variants on gene expression are a major factor for phenotypic variation in complex traits and disease susceptibility. Meanwhile, the protein products of many target genes for the identified cis-regulatory variants (rSNPs) are regulatory molecules themselves (transcription factors, effectors, components of signal transduction pathways, etc.), which implies dramatic downstream effects of these variations on complex gene networks. Here, we brief the results of recent most comprehensive studies on the role of rSNPs in transcriptional regulation across the genome.
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Affiliation(s)
- Vasily M Merkulov
- Laboratory of Gene Expression Regulation, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
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Gengenbach BB, Müschen CR, Buyel JF. Expression and purification of human phosphatase and actin regulator 1 (PHACTR1) in plant-based systems. Protein Expr Purif 2018; 151:46-55. [PMID: 29894805 DOI: 10.1016/j.pep.2018.06.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 05/31/2018] [Accepted: 06/07/2018] [Indexed: 12/21/2022]
Abstract
Cardiovascular diseases are a prevalent cause of morbidity and mortality especially in industrialized countries. The human phosphatase and actin regulator 1 (PHACTR1) may be involved in such diseases, but its precise regulatory function remains unclear due to the large number of potential interaction partners. The same phenomenon makes this protein difficult to express in mammalian cells, but it is also an intrinsically disordered protein that likely aggregates when expressed in bacteria due to the absence of chaperones. We therefore used a design of experiments approach to test the suitability of three plant-based systems for the expression of satisfactory quantities of recombinant PHACTR1, namely transient expression in tobacco (Nicotiana tabacum) BY-2 plant cell packs (PCPs), whole N. benthamiana leaves and BY-2 cell lysate (BYL). The highest yield was achieved using the BYL: up to 120 mg product kg-1 biomass equivalent within 48 h of translation. This was 1.3-fold higher than transient expression in N. benthamiana together with the silencing inhibitor p19, and 6-fold higher than the PCP system. The presence of Triton X-100 in the extraction buffer increased the recovery of PHACTR1 by 2-200-fold depending on the conditions. PHACTR1 was incompatible with biomass blanching and was stable for less than 16 h in raw plant extracts. Purification using a DDK-tag proved inefficient whereas 15% purity was achieved by immobilized metal affinity chromatography.
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Affiliation(s)
- B B Gengenbach
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Forckenbeckstraße 6, 52074, Aachen, Germany.
| | - C R Müschen
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Forckenbeckstraße 6, 52074, Aachen, Germany.
| | - J F Buyel
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Forckenbeckstraße 6, 52074, Aachen, Germany; Institute for Molecular Biotechnology, Worringerweg 1, RWTH Aachen University, 52074, Aachen, Germany.
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Merkulov VM, Leberfarb EY, Merkulova TI. Regulatory SNPs and their widespread effects on the transcriptome. J Biosci 2018. [DOI: 10.1007/s12038-018-9817-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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46
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Abstract
SIGNIFICANCE To maintain homeostasis, gene expression has to be tightly regulated by complex and multiple mechanisms occurring at the epigenetic, transcriptional, and post-transcriptional levels. One crucial regulatory component is represented by long noncoding RNAs (lncRNAs), nonprotein-coding RNA species implicated in all of these levels. Thus, lncRNAs have been associated with any given process or pathway of interest in a variety of systems, including the heart. Recent Advances: Mounting evidence implicates lncRNAs in cardiovascular diseases (CVD) and progression and their presence in the blood of heart disease patients indicates that they are attractive potential biomarkers. CRITICAL ISSUES Our understanding of the regulation and molecular mechanisms of action of most lncRNAs remains rudimentary. A challenge is represented by their often low evolutionary sequence conservation that limits the use of animal models for preclinical studies. Nevertheless, a growing number of lncRNAs with an impact on heart function is rapidly accumulating. In this study, we will discuss (i) lncRNAs that control heart homeostasis and disease; (ii) concepts, approaches, and methodologies necessary to study lncRNAs in the heart; and (iii) challenges posed and opportunities presented by lncRNAs as potential therapeutic targets and biomarkers. FUTURE DIRECTIONS A deeper knowledge of the molecular mechanisms underpinning CVDs is necessary to develop more effective treatments. Further studies are needed to clarify the regulation and function of lncRNAs in the heart before they can be considered as therapeutic targets and disease biomarkers. Antioxid. Redox Signal. 29, 880-901.
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Affiliation(s)
- Simona Greco
- 1 Molecular Cardiology Laboratory, IRCCS Policlinico San Donato , Milan, Italy
| | - Antonio Salgado Somoza
- 2 Cardiovascular Research Unit, Luxembourg Institute of Health (LIH) , Luxembourg, Luxembourg
| | - Yvan Devaux
- 2 Cardiovascular Research Unit, Luxembourg Institute of Health (LIH) , Luxembourg, Luxembourg
| | - Fabio Martelli
- 1 Molecular Cardiology Laboratory, IRCCS Policlinico San Donato , Milan, Italy
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47
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Zhang Z, Jiang F, Zeng L, Wang X, Tu S. PHACTR1 regulates oxidative stress and inflammation to coronary artery endothelial cells via interaction with NF-κB/p65. Atherosclerosis 2018; 278:180-189. [PMID: 30293016 DOI: 10.1016/j.atherosclerosis.2018.08.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 08/06/2018] [Accepted: 08/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Genome-wide association studies have showed that genetic variants in phosphatase and actin regulator 1 (PHACTR1) are associated with coronary artery disease and myocardial infarction. However, the underlying mechanism of PHACTR1 in atherosclerosis remains unknown. METHODS Immunoblots were performed to evaluate the expression of PHACTR1 and phosphorylation of NF-κB signaling. Reactive oxygen species (ROS) labeled with DCFH-DA were assessed by flow cytometry. Fluorescence microscope was used to detect the translocation of p65 in human coronary artery endothelial cells (HACECs). Co-immunoprecipitation was performed to determine the interaction of PHACTR1 with MRTF-A. RESULTS The mRNA and protein levels of PHACTR1 were markedly increased in carotid plaquescompared with normal carotid arteries. Immunofluorescence staining indicated that PHACTR1 was constitutively expressed in endothelial cells in carotid plaques. Knockdown of PHACTR1 reduced excessive ICAM-1, VCAM-1 and VE-cadherin expression induced by oxidized low density lipoprotein (ox-LDL) in HCAECs. Additionally, silencing PHACTR1 alleviated p47phox phosphorylation and intracellular oxidative stress reflected by the reduction of ROS. Molecular experiments revealed that knockdown of PHACTR1 attenuated NF-κB activity without affecting IκBα and IKKα/β phosphorylation. In contrast, nuclear translation of p65 was blocked by depletion of PHACTR1. Furthermore, co-immunoprecipitation showed that PHACTR1 interacted with MRTF-A and p65 in HCAECs. Knockdown of MRTF-A suppressed the interaction of PHACTR1 with p65, subsequently blocking the nuclear translocation of p65. CONCLUSIONS Our finding suggest that silencing PHACTR1 alleviates the nuclear accumulation of p65 and NF-κB via interaction with MRTF-A, ensuing attenuating oxidative stress and inflammation in HCAECs.
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Affiliation(s)
- Zhihui Zhang
- Department of Cardiology, The Third Xiangya Hospital of Central South University, China
| | - Fenglin Jiang
- Department of Cardiology, The Third Xiangya Hospital of Central South University, China
| | - Lixiong Zeng
- Department of Cardiology, The Third Xiangya Hospital of Central South University, China
| | - Xiaoyan Wang
- Department of Cardiology, The Third Xiangya Hospital of Central South University, China
| | - Shan Tu
- Department of Cardiology, The Third Xiangya Hospital of Central South University, China.
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Low‐Kam C, Rhainds D, Lo KS, Barhdadi A, Boulé M, Alem S, Pedneault‐Gagnon V, Rhéaume E, Dubé M, Busseuil D, Hegele RA, Lettre G, Tardif J. Variants at the APOE /C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High-Density Lipoprotein Cholesterol. J Am Heart Assoc 2018; 7:e009545. [PMID: 30369316 PMCID: PMC6201388 DOI: 10.1161/jaha.118.009545] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023]
Abstract
Background Macrophage cholesterol efflux to high-density lipoproteins ( HDLs ) is the first step of reverse cholesterol transport. The cholesterol efflux capacity ( CEC ) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome-wide association study approach, we aimed to identify pathways that regulate CEC in humans. Methods and Results We measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome-wide significant signals ( P<6.25×10-9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology ( CETP , LIPC , LPL , APOA 1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE /C1/C2/C4 variant ( rs141622900, P nonadjusted=1.0×10-11; P adjusted=8.8×10-9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP 1 CB / PLB 1 and RBFOX 3/ ENPP 7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome-wide association study . These analyses identified 27 significant CEC associations, implicating 5 additional loci ( GCKR , LIPG , PLTP , PPARA , and TRIB 1). Conclusions Our genome-wide association study identified common genetic variation at the APOE /C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL -based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.
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Affiliation(s)
| | | | - Ken Sin Lo
- Montreal Heart InstituteMontréalQuébecCanada
| | | | - Marie Boulé
- Montreal Heart InstituteMontréalQuébecCanada
| | - Sonia Alem
- Montreal Heart InstituteMontréalQuébecCanada
| | | | | | | | | | - Robert A. Hegele
- Department of BiochemistryRobarts Research InstituteWestern UniversityLondonOntarioCanada
- Department of MedicineSchulich School of Medicine and DentistryLondonOntarioCanada
| | - Guillaume Lettre
- Montreal Heart InstituteMontréalQuébecCanada
- Faculté de MédecineUniversité de MontréalMontréalQuébecCanada
| | - Jean‐Claude Tardif
- Montreal Heart InstituteMontréalQuébecCanada
- Faculté de MédecineUniversité de MontréalMontréalQuébecCanada
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Abstract
Purpose of Review This review highlights recent findings regarding genetics of coronary artery calcification (CAC), a marker of subclinical atherosclerosis burden, that is a precursor of clinical coronary artery disease. Recent findings CAC quantity is heritable. Genome wide association studies of common single nucleotide polymorphisms have identified genomic regions explaining ~2.4% of CAC heritability. Low frequency and rare variants explain additional variation in CAC. Evidence suggests that there may be different genetic etiologies for variation in CAC progression than for cross-sectional measures of CAC. Studies integrating multiple -omics data are providing new insights into the pathobiology of subclinical coronary atherosclerosis. Summary The future is promising for innovative studies utilizing whole genome sequencing data as well as other -omics such as epigenomic modifications of genes and gene expression. These studies may provide multiple sources of data pointing to the same gene or pathway, thus providing greater confidence in findings.
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Affiliation(s)
- Lawrence F Bielak
- University of Michigan, Department of Epidemiology, School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA
| | - Patricia A Peyser
- University of Michigan, Department of Epidemiology, School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109, USA
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PHACTR1 genotype predicts coronary artery disease in patients with familial hypercholesterolemia. J Clin Lipidol 2018; 12:966-971. [DOI: 10.1016/j.jacl.2018.04.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 04/09/2018] [Accepted: 04/22/2018] [Indexed: 01/09/2023]
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