Common Genetic Variation in MC4R Does Not Affect Atherosclerotic Plaque Phenotypes and Cardiovascular Disease Outcomes.
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ABSTRACT:
SUBMITTER: Blauw LL
PROVIDER: S-EPMC7957774 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIt is unclear whether faster progression of atherosclerosis explains the higher risk of cardiovascular events in CKD. The objectives of this study were to 1. Characterize the associations of CKD with presence and morphology of atherosclerotic plaques on carotid magnetic resonance imaging (MRI) and 2. Examine the associations of baseline CKD and carotid atherosclerotic plaques with subsequent cardiovascular events.MethodsIn a subgroup (N = 465) of Systolic Blood Pressure Intervention Trial. (SPRINT) participants, we measured carotid plaque presence and morphology at baseline and after 30-months with MRI. We examined the associations of CKD (baseline eGFR < 60 ml/min/1.73m2) with progression of carotid plaques and the SPRINT cardiovascular endpoint.ResultsOne hundred and ninety six (42%) participants had CKD. Baseline eGFR in the non-CKD and CKD subgroups were 77 ± 14 and 49 ± 8 ml/min/1.73 m2, respectively. Lipid rich necrotic-core plaque was present in 137 (29.5%) participants. In 323 participants with both baseline and follow-up MRI measurements of maximum wall thickness, CKD was not associated with progression of maximum wall thickness (OR 0.62, 95% CI 0.36 to 1.07, p = 0.082). In 96 participants with necrotic core plaque at baseline and with a valid follow-up MRI, CKD was associated with lower odds of progression of necrotic core plaque (OR 0.41, 95% CI 0.17 to 0.95, p = 0.039). There were 28 cardiovascular events over 1764 person-years of follow-up. In separate Cox models, necrotic core plaque (HR 2.59, 95% CI 1.15 to 5.85) but not plaque defined by maximum wall thickness or presence of a plaque component (HR 1.79, 95% CI 0.73 to 4.43) was associated with cardiovascular events. Independent of necrotic core plaque, CKD (HR 3.35, 95% CI 1.40 to 7.99) was associated with cardiovascular events.ConclusionsPresence of necrotic core in carotid plaque rather than the presence of plaque per se was associated with increased risk of cardiovascular events. We did not find CKD to be associated with faster progression of necrotic core plaques, although both were independently associated with cardiovascular events. Thus, CKD may contribute to cardiovascular disease principally via mechanisms other than atherosclerosis such as arterial media calcification or stiffening.Trial registrationNCT01475747 , registered on November 21, 2011.
| S-EPMC7905597 | biostudies-literature
Project description:Obesity is associated with genetic and environmental factors but the underlying mechanisms remain poorly understood. Recent genome-wide association studies (GWAS) identified obesity- and type 2 diabetes-associated genetic variants located within or near genes that modulate brain activity and development. Among the top hits is rs17782313 near MC4R, encoding for the melanocortin-4-receptor, which is expressed in brain regions that regulate eating. Here, we hypothesized rs17782313-associated changes in human brain regions that regulate eating behavior. Therefore, we examined effects of common variants at rs17782313 near MC4R on brain structure and eating behavior. Only in female homozygous carriers of the risk allele we found significant increases of gray matter volume (GMV) in the right amygdala, a region known to influence eating behavior, and the right hippocampus, a structure crucial for memory formation and learning. Further, we found bilateral increases in medial orbitofrontal cortex, a multimodal brain structure encoding the subjective value of reinforcers, and bilateral prefrontal cortex, a higher order regulation area. There was no association between rs17782313 and brain structure in men. Moreover, among female subjects only, we observed a significant increase of 'disinhibition', and, more specifically, on 'emotional eating' scores of the Three Factor Eating Questionnaire in carriers of the variant rs17782313's risk allele. These findings suggest that rs17782313's effect on eating behavior is mediated by central mechanisms and that these effects are sex-specific.
| S-EPMC3774636 | biostudies-literature
Project description:Carotid artery plaque is a measure of atherosclerosis and is associated with future risk of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary, cerebrovascular, and peripheral arterial diseases. With advanced imaging techniques, computerized tomography (CT) and magnetic resonance imaging (MRI) have shown their potential superiority to routine ultrasound to detect features of carotid plaque vulnerability, such as intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), fibrous cap (FC), and calcification. The correlation between imaging features and histological changes of carotid plaques has been investigated. Imaging of carotid features has been used to predict the risk of cardiovascular events. Other techniques such as nuclear imaging and intra-vascular ultrasound (IVUS) have also been proposed to better understand the vulnerable carotid plaque features. In this article, we review the studies of imaging specific carotid plaque components and their correlation with risk scores.
| S-EPMC7487384 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICIs) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events.MethodsThe study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls matched by age, a history of cardiovascular events, and cancer type. In a second design, a case-crossover analysis was performed with an at-risk period defined as the 2-year period after and the control period as the 2-year period before treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. All study measures and outcomes were blindly adjudicated.ResultsIn the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (hazard ratio, 3.3 [95% CI, 2.0-5.5]; P<0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio, 4.8 [95% CI, 3.5-6.5]; P<0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/y before 6.7%/y after). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids.ConclusionsCardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk before, during, and after treatment should be considered among patients on an ICI.
| S-EPMC7736526 | biostudies-literature
Project description:ObjectiveAlthough plaque erosion causes approximately 40% of all coronary thrombi and disproportionally affects women more than men, its mechanism is not well understood. The role of tissue mechanics in plaque rupture and regulation of mechanosensitive inflammatory proteins is well established, but their role in plaque erosion is unknown. Given obvious differences in morphology between plaque erosion and rupture, we hypothesized that inflammation in general as well as the association between local mechanical strain and inflammation known to exist in plaque rupture may not occur in plaque erosion. Therefore, our objective was to determine if similar mechanisms underlie plaque rupture and plaque erosion.Methods and resultsWe studied a total of 74 human coronary plaque specimens obtained at autopsy. Using lesion-specific computer modeling of solid mechanics, we calculated the stress and strain distribution for each plaque and determined if there were any relationships with markers of inflammation. Consistent with previous studies, inflammatory markers were positively associated with increasing strain in specimens with rupture and thin-cap fibroatheromas. Conversely, overall staining for inflammatory markers and apoptosis were significantly lower in erosion, and there was no relationship with mechanical strain. Samples with plaque erosion most closely resembled those with the stable phenotype of thick-cap fibroatheromas.ConclusionsIn contrast to classic plaque rupture, plaque erosion was not associated with markers of inflammation and mechanical strain. These data suggest that plaque erosion is a distinct pathophysiological process with a different etiology and therefore raises the possibility that a different therapeutic approach may be required to prevent plaque erosion.
| S-EPMC4218818 | biostudies-literature
Project description:Aberrantly expressed miRNAs contribute to developmental abnormalities and diseases such as cancer, diabetes, and cardiovascular disorders, by hybridizing to specific mRNA targets and repressing their translation into proteins. Although miRNA expression signature is characterized in the process of neointimal thickening during proliferative vascular diseases such as atherosclerosis, so far global miRNA expression profiling in the different stages of atherosclerosis is completely unknown. We explored stage-specific microRNA signatures in the progress of atherosclerosis in hyperlipidemia mouse model, which may help to identify the critical miRNAs contributing atherosclerotic development and stabilization. Female apoe-/- mice (6-8 weeks, Jackson Laboratory) were fed a high fat diet (HFD, 21% crude fat, 0.15% cholesterol and 19.5% casein, Altromin, Germany) for 3 or 10 months (N=3-4). Serial sections (20 µm thick) of aortic roots and carotid arteries from these mice were mounted on membrane mounted metal frame slides (MMI), deparaffinized under RNase-free conditions, and completely dried. Laser capture microdissection (LCM) was performed with a laser microdissection system (MMI cellcut plus, Molecular Machines and Industries, Switzerland) assembled onto an inverted microscope (Olympus IX71). Plaque tissue or morphologically normal vessel wall of at least 40 sections per mouse were collected. RNA was isolated using RecoverAll total nucleic acid isolation kit (Applied Biosystems) according to the manufacturer’s instructions.
2013-03-27 | E-GEOD-34647 | biostudies-arrayexpress
Project description:Genome-wide association studies (GWAS) have uncovered many genetic associations for cardiovascular disease (CVD). However, data are limited regarding causal genetic variants within implicated loci. We sought to identify regulatory variants (cis- and trans-eQTLs) affecting expression levels of 93 genes selected by their proximity to SNPs with significant associations in prior GWAS for CVD traits. Expression levels were measured by qRT-PCR in leukocytes from 1846 Framingham Heart Study participants. An additive genetic model was applied to 2.5 million imputed SNPs for each gene. Approximately 45% of genes (N = 38) harbored at least one cis-eSNP after a regional multiple-test adjustment. Applying a more rigorous significance threshold (P < 5 × 10(-8)), we found the expression level of 10 genes was significantly associated with more than one cis-eSNP. The top cis-eSNPs for 7 of these 10 genes exhibited moderate-to-strong association with ? 1 CVD clinical phenotypes. Several eSNPs or proxy SNPs (r(2) = 1) were replicated by other eQTL studies. After adjusting for the lead GWAS SNPs for the 10 genes, expression variances explained by top cis-eSNPs were attenuated markedly for LPL, FADS2 and C6orf184, suggesting a shared genetic basis for the GWAS and expression trait. A significant association between cis-eSNPs, gene expression and lipid levels was discovered for LPL and C6orf184. In conclusion, strong cis-acting variants are localized within nearly half of the GWAS loci studied, with particularly strong evidence for a regulatory role of the top GWAS SNP for expression of LPL, FADS2 and C6orf184.
| S-EPMC3900869 | biostudies-literature
Project description:UnlabelledOsteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n?=?1061) and OPRA (age 75, n?=?1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2)?=?0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs.Cc bua100 vs. 103 vs. 103; p?=?0.002); (SOS: 1521 vs. 1526 vs. 1524; p?=?0.008); (Stiffness index: 69 vs. 73 vs. 74; p?=?0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p?=?0.03) and vitamin D (93 vs. 91 vs. 90; p?=?0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p?=?0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p?=?0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p?0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.
| S-EPMC3916440 | biostudies-literature
Project description:Clustering of obesity, coronary artery disease, and cardiovascular disease risk factors is observed in epidemiological studies and clinical settings. Twin and family studies have provided some supporting evidence for the clustering hypothesis. Loci nearest a lead single nucleotide polymorphism (SNP) showing genome-wide significant associations with coronary artery disease, body mass index, C-reactive protein, blood pressure, lipids, and type 2 diabetes mellitus were selected for pathway and network analyses. Eighty-seven autosomal regions (181 SNPs), mapping to 56 genes, were found to be pleiotropic. Most pleiotropic regions contained genes associated with coronary artery disease and plasma lipids, whereas some exhibited coaggregation between obesity and cardiovascular disease risk factors. We observed enrichment for liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor/RXR nuclear receptor signaling among pleiotropic genes and for signatures of coronary artery disease and hepatic steatosis. In the search for functionally interacting networks, we found that 43 pleiotropic genes were interacting in a network with an additional 24 linker genes. ENCODE (Encyclopedia of DNA Elements) data were queried for distribution of pleiotropic SNPs among regulatory elements and coding sequence variations. Of the 181 SNPs, 136 were annotated to ≥ 1 regulatory feature. An enrichment analysis found over-representation of enhancers and DNAse hypersensitive regions when compared against all SNPs of the 1000 Genomes pilot project. In summary, there are genomic regions exerting pleiotropic effects on cardiovascular disease risk factors, although only a few included obesity. Further studies are needed to resolve the clustering in terms of DNA variants, genes, pathways, and actionable targets.
| S-EPMC4416656 | biostudies-literature
Project description:BackgroundThe hallmark of atherosclerosis is the accumulation of plaque in vessel walls. This process is initiated when monocytic cells differentiate into macrophage foam cells under conditions with high levels of atherogenic lipoproteins. Vulnerable plaque can dislodge, enter the blood stream, and result in acute myocardial infarction and stroke. Imaging techniques such as cardiovascular magnetic resonance (CMR) provides one strategy to identify patients with plaque accumulation.MethodsWe synthesized an atherosclerotic-targeting contrast agent (ATCA) in which gadolinium (Gd)-containing endohedrals were functionalized and formulated into liposomes with CD36 ligands intercalated into the lipid bilayer. In vitro assays were used to assess the specificity of the ATCA for foam cells. The ability of ATCA to detect atherosclerotic plaque lesions in vivo was assessed using CMR.ResultsThe ATCA was able to detect scavenger receptor (CD36)-expressing foam cells in vitro and were specifically internalized via the CD36 receptor as determined by focused ion beam/scanning electron microscopy (FIB-SEM) and Western blotting analysis of CD36 receptor-specific signaling pathways. The ATCA exhibited time-dependent accumulation in atherosclerotic plaque lesions of ApoE -/- mice as determined using CMR. No ATCA accumulation was observed in vessels of wild type (C57/b6) controls. Non-targeted control compounds, without the plaque-targeting moieties, were not taken up by foam cells in vitro and did not bind plaque in vivo. Importantly, the ATCA injection was well tolerated, did not demonstrate toxicity in vitro or in vivo, and no accumulation was observed in the major organs.ConclusionsThe ATCA is specifically internalized by CD36 receptors on atherosclerotic plaque providing enhanced visualization of lesions under physiological conditions. These ATCA may provide new tools for physicians to non-invasively detect atherosclerotic disease.
| S-EPMC3562260 | biostudies-literature