Sirtuin/uncoupling protein gene variants and carotid plaque area and morphology.
Ontology highlight
ABSTRACT:
SUBMITTER: Dong C
PROVIDER: S-EPMC6561468 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Sirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through the control of reactive oxygen species production. This study sought to investigate the association between genetic variants in the SIRT and UCP genes and carotid plaque.In a group of 1018 stroke-free subjects from the Northern Manhattan Study with high-definition carotid ultrasonography and genotyping, we investigated the associations of 85 single nucleotide polymorphisms (SNPs) in the 11 SIRT and UCP genes with the presence and number of carotid plaques, and evaluated interactions of SNPs with sex, smoking, diabetes and hypertension as well as interactions between SNPs significantly associated with carotid plaque.Overall, 60% of subjects had carotid plaques. After adjustment for demographic and vascular risk factors, T-carriers of the SIRT6 SNP rs107251 had an increased risk for carotid plaque (odds ratio, OR?=?1.71, 95% CI?=?1.23-2.37, Bonferroni-corrected p?=?0.03) and for a number of plaques (rate ratio, RR?=?1.31, 1.18-1.45, Bonferroni-corrected p?=?1.4×10(-5)), whereas T-carriers of the UCP5 SNP rs5977238 had an decreased risk for carotid plaque (OR?=?0.49, 95% CI?=?0.32-0.74, Bonferroni-corrected p?=?0.02) and plaque number (RR?=?0.64, 95% CI?=?0.52-0.78, Bonferroni-corrected p?=?4.9×10(-4)). Some interactions with a nominal p?0.01 were found between sex and SNPs in the UCP1 and UCP3 gene; between smoking, diabetes, hypertension and SNPs in UCP5 and SIRT5; and between SNPs in the UCP5 gene and the UCP1, SIRT1, SIRT3, SIRT5, and SIRT6 genes in association with plaque phenotypes.We observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque. We also found potential effect modifications by sex, smoking and vascular risk factors of the SIRT/UCP genes in the associations with atherosclerotic plaque. Further studies are needed to validate our observations.
| S-EPMC3210138 | biostudies-literature
Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies.
2011-10-01 | GSE24495 | GEO
Project description:In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content. A smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies. 6 human carotid plaques were sectioned in 1 mm thick slices. Alternative slices were used for gene expression profiling in Affymetrix/Merck custom 1.0 arrays (GPL10687), or for immunohistochemistry studies (CD68, Actin)
2011-09-30 | E-GEOD-24495 | biostudies-arrayexpress
Project description:BackgroundChronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP).MethodsPatients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin.ResultsCarotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m2. Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking).ConclusionsThe higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought.
| S-EPMC7450288 | biostudies-literature
Project description:BackgroundPeriodontal disease (PD) is a chronic inflammatory oral condition with potentially important systemic sequelae. We sought to determine whether the presence of PD in patients with severe carotid disease was associated with morphological features consistent with carotid plaque instability.MethodsA total of 52 dentate patients hospitalized for carotid endarterectomy (CEA) had standardized assessments of their periodontal status, including measurements of probing pocket depth (PPD), clinical attachment level (CAL) and bleeding on probing (BoP). Carotid plaque morphology was assessed by ultrasound using the gray scale median (GSM) score and by immunohistochemistry using anti-CD68 and anti-alpha-actin antibodies, markers for macrophages and smooth muscle cells (SMCs) respectively.ResultsIn total 30/52 patients (58%) had PD. Significant associations were noted between low GSM on ultrasound and each mm in PPD (p = 0.001), each mm in CAL (p = 0.002) and with a 10% increase in BoP (p = 0.009). Using the standardized PERIO definition the association remained robust (aOR = 10.4 [95% CI:2.3-46.3], p = .002). Significant associations were also observed with high macrophage accumulation and each individual PD measure (p < 0.01 for PPD, CAL and BoP) and with the PERIO definition (aOR = 15 [95% CI:1.8-127.8], p = .01). Similarly, low SMC density was also significantly associated with individual measures of PD (p < 0.05 for PPD, CAL and BoP), but not with the PERIO definition (aOR 3.4 [95% CI:0.9-12.8], p = .07).ConclusionsThe presence of PD was significantly associated with both ultrasound and immunohistochemistry features of carotid plaque instability in patients undergoing CEA.
| S-EPMC7419330 | biostudies-literature
Project description:Studies have linked elevated total homocysteine (tHcy) levels to atherosclerotic carotid plaque development, but data are limited to predominantly white populations. We examined the association between tHcy and carotid plaque burden and morphology in a multiethnic cohort.In the Northern Manhattan Study, we conducted a cross-sectional analysis among 1327 stroke-free subjects (mean age, 66 ± 9; 41% men; 19% black; 62% Hispanic; 17% white) with serum tHcy and ultrasonographic assessment of plaque morphology measured by gray-scale median (GSM) and total plaque area (TPA). GSM and TPA were examined in 4 categories. High and low GSM categories were considered echodense and echolucent plaque, respectively, and compared with no plaque. Logistic regression models were used to assess the associations of tHcy with GSM and TPA adjusting for demographics, vascular risk factors, renal insufficiency, and B(12) deficiency.The mean tHcy was 9.4 ± 4.8 µmol/L (median=8.6). The prevalence of carotid plaque was 57% (52% among Hispanics, 58% black, and 70% white). Among those with plaque, the mean TPA was 20.3 ± 20.6 mm(2) (median=13.6) and mean GSM 90.9 ± 28.5 (median=93.0). The top 2 tHcy quartiles (versus quartile 1) had an elevated risk of having either echolucent plaque (tHcy Q3, odds ratio [OR]=1.8; [95% confidence interval {CI} 1.2-2.8]; tHcy Q4, OR=1.9 [95% CI 1.2-3.1]) or echodense plaque (tHcy Q3, OR=1.7 [95% CI, 1.1-2.7]; tHcy Q4, OR=1.9 [95% CI, 1.2-3.2]). The top 2 tHcy quartiles were also more likely to be in the highest TPA category (tHcy Q3, OR=1.8 [95% CI, 1.1-3.0]; tHcy Q4, OR=2.2 [95% CI, 1.3-3.7]).In this population-based multiethnic cohort, elevated tHcy was independently associated with plaque morphology and increased plaque area, subclinical markers of stroke risk.
| S-EPMC3567916 | biostudies-literature
Project description:This study aims to explore the relationship between plaque surface morphology and neovascularization using a high temporal and spatial resolution 4D contrast-enhanced MRI/MRA sequence.Twenty one patients with either recent symptoms or a carotid artery stenosis ≥40% were recruited in this study. Plaque surface morphology and luminal stenosis were determined from the arterial phase MRA images. Carotid neovascularization was evaluated by a previously validated pharmacokinetic (PK) modeling approach. K trans (transfer constant) and v p (partial plasma volume) were calculated in both the adventitia and plaque.Image acquisition and analysis was successfully performed in 28 arteries. Mean luminal stenosis was 44% (range 11-82%). Both adventitial and plaque K trans in ulcerated/irregular plaques were significantly higher than smooth plaques (0.079 ± 0.018 vs. 0.064 ± 0.011 min-1, p = 0.02; 0.065 ± 0.013 vs. 0.055 ± 0.010 min-1, p = 0.03, respectively). Positive correlations between adventitial K trans and v p against stenosis were observed (r = 0.44, p = 0.02; r = 0.55, p = 0.01, respectively).This study demonstrates the feasibility of using a single sequence to acquire both high resolution 4D CE-MRA and DCE-MRI to evaluate both plaque surface morphology and function. The results demonstrate significant relationships between lumen surface morphology and neovascularization.
| S-EPMC5813060 | biostudies-other
Project description:RationaleRemodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex processes evolves, there is a need to develop new imaging techniques to study underlying mechanisms.ObjectiveWe used tissue clearing and light-sheet microscopy for 3-dimensional (3D) profiling of the vascular response to carotid artery ligation and induction of atherosclerosis in mouse models.Methods and resultsAdipo-Clear and immunolabeling in combination with light-sheet microscopy were applied to image carotid arteries and brachiocephalic arteries, allowing for 3D reconstruction of vessel architecture. Entire 3D neointima formations with different geometries were observed within the carotid artery and scored by volumetric analysis. Additionally, we identified a CD31-positive adventitial plexus after ligation of the carotid artery that evolved and matured over time. We also used this method to characterize plaque extent and composition in the brachiocephalic arteries of ApoE-deficient mice on high-fat diet. The plaques exhibited inter-animal differences in terms of plaque volume, geometry, and ratio of acellular core to plaque volume. A 3D reconstruction of the endothelium overlying the plaque was also generated.ConclusionsWe present a novel approach to characterize vascular remodeling in adult mice using Adipo-Clear in combination with light-sheet microscopy. Our method reconstructs 3D neointima formation after arterial injury and allows for volumetric analysis of remodeling, in addition to revealing angiogenesis and maturation of a plexus surrounding the carotid artery. This method generates complete 3D reconstructions of atherosclerotic plaques and uncovers their volume, geometry, acellular component, surface, and spatial position within the brachiocephalic arteries. Our approach may be used in a number of mouse models of cardiovascular disease to assess vessel geometry and volume. Visual Overview: An online visual overview is available for this article.
| S-EPMC7047629 | biostudies-literature
Project description:ObjectiveElevated fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis, has been associated with mortality, cardiovascular events, and stroke, and to arterial calcification in chronic kidney disease, but its role in atherosclerosis is unclear and population-based studies are lacking. We hypothesized that elevated FGF23 would associate with carotid plaque presence, area, and echogenicity in the race/ethnically diverse community-based Northern Manhattan Study (NOMAS) sample.Approach and resultsThere were 1512 stroke-free NOMAS participants with FGF23 and 2-dimensional carotid ultrasound data (mean age, 68±9 years; 61% women; 62% Hispanic, 18% black, and 18% white). We used multivariable linear and logistic regression to evaluate FGF23, continuously and by quintiles, as a correlate of carotid plaque, plaque area (cubic root transformed), and echogenicity adjusting for sociodemographic and vascular risk factors. Participants with FGF23 levels in the top quintile were more likely to have carotid plaque (odds ratio, 1.49; 95% confidence interval, 1.02-2.19; P=0.04) and larger plaque area (β=0.32 mm(2), 95% confidence interval, 0.10-0.53 mm(2); P=0.004) than those in the lowest quintile, adjusting for estimated glomerular filtration rate, demographics, and vascular risk factors. Linear regression models also showed that log transformed FGF23 (LnFGF23) associated with greater odds of plaque presence (odds ratio, 1.26 per LnFGF23; 95% confidence interval, 1.01-1.58; P=0.04), and plaque area (β=0.19 mm(2) per LnFGF23; 95% confidence interval, 0.07-0.31 mm(2); P=0.002).ConclusionsHigher FGF23 associated with greater likelihood and burden of carotid atherosclerosis independent of CKD. Atherosclerosis may be a mechanism through which FGF23 increases cardiovascular events and stroke.
| S-EPMC4552577 | biostudies-literature
Project description:Background and purposeSmoking greatly increases the risk of atherosclerotic plaque and the effect may vary from individual to individual. A genome-wide scan was performed for smoking×single nucleotide polymorphism (SNP) interactions on carotid plaque burden (CPB) to identify the potential genetic moderators in Hispanics.MethodsCarotid B-mode ultrasonography and genotyping by the Affymetrix 6.0 chip were performed in a discovery sample of 665 Caribbean Hispanics, followed by replication analyses in 264 Caribbean Hispanics. CPB was expressed as the sum of plaque areas over the segments in common and internal carotid arteries and bifurcation. Smoking was classified as 0, <20, and ≥20 cigarette pack-years. Assuming an additive genetic model, regression analysis was conducted to test for smoking×SNP interaction on the cube root transformed CPB while controlling for age, sex, and the top 3 principal components of ancestry.ResultsTwo SNPs showed a significant interaction with smoking on CPB with the similar effects in both discovery (P<1.0E-5) and replication (P<0.05) populations. Specifically, for SNP rs10205487 within MXD1, more smoking was significantly associated with greater CPB in A allele carriers (beta±SE: 0.24±0.08, P=0.005 in AG carriers; beta±SE: 0.48±0.12, P=0.0002 in AA carriers) but not in GG (P=0.06). For SNP rs7001413 within LY96 and JPH1, more smoking was significantly associated with greater CPB in GG carriers (beta±SE: 0.24±0.06, P=6.8E-5) but not in T carriers (P=0.06).ConclusionsOur study suggests that genetic variants may modulate the effect of smoking on CPB and highlights several genes for further investigation of their role in atherosclerosis, especially in smoking population.
| S-EPMC4143440 | biostudies-literature