Causal Gene Confusion: The Complicated EDN1/PHACTR1 Locus for Coronary Artery Disease.
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ABSTRACT:
SUBMITTER: Gupta RM
PROVIDER: S-EPMC9050840 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
Publications
Causal Gene Confusion: The Complicated <i>EDN1/PHACTR1</i> Locus for Coronary Artery Disease.
Arteriosclerosis, thrombosis, and vascular biology 20220407 5
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Project description:BackgroundSpontaneous 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.ObjectivesThis study sought to test the association between the rs9349379 genotype and SCAD.MethodsResults 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.ResultsThe 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.ConclusionsThe 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.
| S-EPMC10403154 | biostudies-literature
Project description:Recent genome-wide association studies have identified PHACTR1 as a critical risk gene associated with polyvascular diseases. However, it remains elusive how PHACTR1 is involved in endothelial dysfunction. Here, we show that PHACTR1 triggers endothelial inflammation by activating NF-κB and disrupts Nitric oxide production by inhibiting Akt/eNOS activation to induce endothelial diastolic disorder. Whereas, Atorvastatin particularly plays an inhibitory effect on PHACTR1 gene expression in a dose-dependent manner among PHACTR family in endothelial cells. PHACTR1 may interact with PP1 with coupling with heat shock protein 8 (HSPA8) to dephosphorylate Akt or eNOS.
2022-08-16 | PXD034213 | Pride
Project description: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.
| S-EPMC9457086 | biostudies-literature
Project description:Single-nucleotide polymorphisms (SNPs) in the protein phosphatase and actin regulator 1 gene (PHACTR1) have been associated with susceptibility to develop several diseases, including cardiovascular disease. The purpose of this study was to evaluate the role of two polymorphisms (rs2026458 and rs9349379) of the PHACTR1 gene in the susceptibility to the risk of developing premature coronary artery disease (CAD) in the Mexican population. The genotype analysis was performed using 5'exonuclease TaqMan genotyping assays in a group of 994 patients with premature CAD and 703 controls. A similar genotype distribution of rs2026458 was observed in both groups; however, under an additive model adjusted by age, body mass index, type 2 diabetes mellitus, smoking, dyslipidemia, and hypertension, the rs9349379 G allele was associated with a higher risk for developing premature CAD (odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.03-1.46, p-value (p) = 0.024). The two PHACTR1 polymorphisms were not in linkage disequilibrium. In summary, our results suggest that the PHACTR1 rs9349379 polymorphism plays an important role in the risk of developing premature CAD in the Mexican population.
| S-EPMC4997489 | biostudies-literature
Project description:BackgroundSevere coronary artery disease (CAD) represents an advanced arterial narrowing, often associated with critical complications like myocardial infarction and angina. This study aimed to comprehensively investigate determinants of severe and multi-vessel CAD manifestations.MethodsOne thousand nine hundred patients with severe and multivessel CAD (stenosis > 70%) were recruited along with 1,056 controls without stenosis. Associations using a genotyping panel comprising 159 Single Nucleotide Polymorphisms (SNPs) previously implicated in CAD pathogenesis were examined and these associations were replicated using the UK Biobank cohort (N = 29,970).ResultsThe investigation identified 14 genetic associations with severe CAD, of which 7 were also associated with multivessel disease. Notably, PHACTR1 SNP (rs9349379*G) showed a higher association with severe and multivessel CAD in individuals aged ≤ 65, indicating a higher risk of early disease onset. Conversely, the APOC1/APOE SNP (rs445925*T) is associated with reduced susceptibility to severe CAD and multivessel disease in individuals aged over 65, indicating a persistent negative association.ConclusionsFollowing replication of the associations in the large UK Biobank dataset, it was found that patients carrying the rs9349379*G variant in the PHACTR1 gene are at risk of developing severe or multivessel disease. Conversely, the rs445925*T variant in APOC1/APOE is associated with reduced susceptibility to severe CAD and multivessel disease, highlighting the significance of this genetic variant in these specific CAD presentations. This study contributes to a better understanding of CAD heterogeneity, paving the way for tailored management strategies based on genetic profiles.
| S-EPMC11471027 | biostudies-literature
Project description:Previous studies showed that PHACTR1 and SLC22A3 are involved in coronary vascular development and are key determinants of cardiovascular disease risk. We conducted a case-control study to examine the effect of SLC22A3 and PHACTR1 single nucleotide polymorphisms (SNPs) on CAD risk among 376 male CAD patients and 388 male healthy controls from China. Eleven SLC22A3 and PHACTR1 SNPs were selected and genotyped using Sequenom Mass-ARRAY technology. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age. The rs9381439 minor allele "A" (OR = 0.72; 95% CI = 0.54-0.96; p = 0.024) in an allelic model was associated with reduced CAD risk, as were the rs2048327 "C/C" (OR = 0.60; 95% CI: 0.37-0.97; p = 0.036) and rs1810126 "T/T" (OR = 0.58; 95% CI: 0.36-0.93; p = 0.024) genotypes. Likewise, the rs9349379 "A/G" genotype in a dominant model (p = 0.041), the rs1810126 "T/C" genotype in additive (p = 0.041) and recessive (p = 0.012) models, and the rs2048327 "C/T" genotype in a recessive model were associated with decreased CAD risk (p = 0.016). These results suggest several PHACTR1 and SLC22A3 polymorphisms are associated with decreased CAD risk in the male Chinese Han population.
| S-EPMC5352186 | biostudies-literature
Project description:Endothelin-1 (ET-1) plays important roles in endothelial dysfunction, vascular physiology, inflammation, and atherosclerosis. Nonetheless, the role of ET-1 (EDN1) gene variants on coronary artery disease (CAD) risk remains poorly understood. The aim of the present study was to evaluate the role of EDN1 gene polymorphisms on individual susceptibility to CAD. We genotyped five tagSNPs (single-nucleotide polymorphisms) (rs6458155, rs4145451, rs9369217, rs3087459, and rs2070699) within EDN1 gene in 525 CAD patients and 675 control subjects. In a multivariate logistic regression analysis, we detected an association of rs6458155 in EDN1 gene with the CAD risk; compared with the TT homozygotes, the CT heterozygotes (odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.02-2.29, P=0.040) and the CC homozygotes (OR = 1.55, 95% CI = 1.01-2.36, P=0.043) were statistically significantly associated with the increased risk for CAD. A similar trend of the association was found in dominant model (OR = 1.53, 95% CI = 1.05-2.25, P=0.029). Consistently, the haplotype rs6458155C-rs4145451C containing rs6458155 C allele exhibited the increased CAD risk (OR = 1.22, 95% CI = 1.03-1.43, and P=0.018). In addition, CT genotype of rs6458155 conferred the increased plasma ET-1 levels compared with TT genotype (P<0.05). No association of the other four tagSNPs in EDN1 gene with CAD risk was observed. In conclusion, our study provides the first evidence that EDN1 tagSNP rs6458155 is associated with CAD risk in the Chinese Han population, which is probably due to the influence of the circulating ET-1 levels.
| S-EPMC6205642 | biostudies-literature
Project description:BackgroundHundreds of candidate genes have been associated with coronary artery disease (CAD) through genome-wide association studies. However, a systematic way to understand the causal mechanism(s) of these genes, and a means to prioritize them for further study, has been lacking. This represents a major roadblock for developing novel disease- and gene-specific therapies for patients with CAD. Recently, powerful integrative genomics analyses pipelines have emerged to identify and prioritize candidate causal genes by integrating tissue/cell-specific gene expression data with genome-wide association study data sets.MethodsWe aimed to develop a comprehensive integrative genomics analyses pipeline for CAD and to provide a prioritized list of causal CAD genes. To this end, we leveraged several complimentary informatics approaches to integrate summary statistics from CAD genome-wide association studies (from UK Biobank and CARDIoGRAMplusC4D) with transcriptomic and expression quantitative trait loci data from 9 cardiometabolic tissue/cell types in the STARNET study (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task).ResultsWe identified 162 unique candidate causal CAD genes, which exerted their effect from between one and up to 7 disease-relevant tissues/cell types, including the arterial wall, blood, liver, skeletal muscle, adipose, foam cells, and macrophages. When their causal effect was ranked, the top candidate causal CAD genes were CDKN2B (associated with the 9p21.3 risk locus) and PHACTR1; both exerting their causal effect in the arterial wall. A majority of candidate causal genes were represented in cross-tissue gene regulatory co-expression networks that are involved with CAD, with 22/162 being key drivers in those networks.ConclusionsWe identified and prioritized candidate causal CAD genes, also localizing their tissue(s) of causal effect. These results should serve as a resource and facilitate targeted studies to identify the functional impact of top causal CAD genes.
| S-EPMC8847335 | biostudies-literature
Project description:Background and objectiveCoronary artery disease (CAD) is a major cause of death worldwide. Revascularization via stent placement or coronary artery bypass grafting (CABG) are standard treatments for CAD. Despite a high success rate, these approaches are associated with long-term failure due to restenosis. Risk factors associated with restenosis were investigated using a case-control association study design.MethodsFive thousand two hundred and forty-two patients were enrolled in this study and were assigned as follows: Stenosis Group: 3570 patients with CAD >50% without a prior stent or CABG (1394 genotyped), and Restenosis Group: 1672 patients with CAD >50% and prior stent deployment or CABG (705 genotyped). Binomial regression models were applied to investigate the association of restenosis with diabetes, hypertension, and dyslipidemia. The genetic association with restenosis was conducted using PLINK 1.9.ResultsDyslipidemia is a major risk factor (Odds Ratio (OR) = 2.14, P-value <0.0001) for restenosis particularly among men (OR = 2.32, P < 0.0001), while type 2 diabetes (T2D) was associated with an increased risk of restenosis in women (OR = 1.36, P = 0.01). The rs9349379 (PHACTR1) and rs264 (LPL) were associated with an increased risk of restenosis in our patients. PHACTR1 variant was associated with increased risk of restenosis mainly in women and in diabetic patients, while the LPL variant was associated with increased risk of restenosis in men.ConclusionThe rs9349379 in PHACTR1 gene is significantly associated with restenosis, this association is more pronounced in women and in diabetic patients. The rs264 in LPL gene was associated with increased risk of restenosis in male patients.
| S-EPMC9940491 | biostudies-literature
Project description:BackgroundGenome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the FES (FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis.Methods and resultsAnalyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed FES were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed FES. There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that Fes knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet.ConclusionsWe provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.
| S-EPMC9770135 | biostudies-literature