Association of Genetic Polymorphisms in the Matrix Gla Protein (MGP) Gene with Coronary Artery Disease and Serum MGP Levels.
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SUBMITTER: Karsli-Ceppioglu S
PROVIDER: S-EPMC6956629 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Matrix Gla protein (MGP) is a key regulator of vascular calcification. Genetic variation at the MGP locus could modulate the development of coronary artery calcification (CAC). Our aim was to examine the cross-sectional association between MGP single nucleotide polymorphisms (SNPs) [rs1800802 (T-138C), rs1800801 (G-7A), and rs4236 (Ala102Thr)] and CAC. CAC was measured by multidetector computed tomography (MDCT), in older men and women of European descent, (n=386; 60 to 80 y of age). Serum MGP was measured by radioimmunoassay. Linear, Tobit and Ordinal regression analyses all revealed that in men, homozygous carriers of the minor allele of rs1800802, rs1800801, or rs4236 (minor allele frequency: 21, 38, and 40%, respectively) were associated with a decreased quantity of CAC, relative to major allele carriers. This association was not found in women. Although genetic variation in MGP was associated with serum MGP concentrations, there were no associations between serum MGP and CAC. The results of this study suggest a role for MGP genetic variants in coronary atherosclerosis among men that is not reflected in serum MGP concentrations.
| S-EPMC2706526 | biostudies-literature
Project description:BackgroundOsteoarthritis (OA) is a common disease of older individuals that impacts detrimentally on the quality and the length of life. It is characterised by the painful loss of articular cartilage and is polygenic and multifactorial. Genome-wide association scans have highlighted over 90 osteoarthritis genetic signals, some of which reside within or close to highly plausible candidate genes. An example is an association to polymorphisms within and adjacent to the matrix Gla protein gene MGP. We set out to undertake a functional study of this gene.MethodsNucleic acid was extracted from cartilage, infrapatellar fat pad, synovium, trabecular bone, trapezium and peripheral whole blood from OA patients and also from mesenchymal stem cells (MSCs) subjected to chondrogenesis. Expression of MGP was measured by quantitative PCR (qPCR), RNA-sequencing and allelic expression imbalance (AEI) analysis. Matrix Gla protein was depleted in chondrocytes by knocking down MGP expression using RNA interference (RNAi) and the effect on a range of genes assessed by qPCR.ResultsMGP is expressed in joint tissues, blood and chondrocytes cultured from MSCs. There is a higher expression in diseased versus non-diseased cartilage. Polymorphisms that are associated with OA also correlate with the expression of MGP, with the OA risk-conferring allele showing significantly reduced expression in cartilage, fat pad and synovium but increased expression in blood. Depletion of Matrix Gla protein had a significant effect on the majority of genes tested, with an increased expression of catabolic genes that encode enzymes that degrade cartilage.ConclusionsMGP expression is subject to cis-acting regulators that correlate with the OA association signal. These are active in a range of joint tissues but have effects which are particularly strong in cartilage. An opposite effect is observed in blood, highlighting the context-specific nature of the regulation of this gene's expression. Recapitulation of the genetic deficit in cartilage chondrocytes is pro-catabolic.
| S-EPMC6582465 | biostudies-literature
Project description:Low levels of the antioxidative serum bilirubin are associated with vascular aging and an increased risk for coronary artery disease (CAD). UGT1A1 is the major gene influencing bilirubin concentrations. Therefore, we investigated an association of bilirubin levels and two polymorphisms in the promoter of UGT1A1 (-53(TA-repeat) polymorphism and T-3279G) in 477 patients with premature, familial CAD and 619 age- and sex-matched controls. Bilirubin concentrations were significantly lower in cases than in controls (0.62+/-0.36 vs. 0.76+/-0.41 mg/dl for men, p=1.2 x 10(-10); and 0.42+/-0.29 vs. 0.55+/-0.23 mg/dl, p=1.9 x 10(-9) for women). Both polymorphisms showed a strong association with bilirubin levels with higher levels for homozygote carriers of the minor allele. These associations were most pronounced in male controls and patients (p=5.9 x 10(-26) and p=3.4 x 10(-16), respectively, for the -53(TA-repeat) polymorphism). Logistic regression analysis revealed low bilirubin levels but not the UGT1A1 polymorphisms to be significantly associated with CAD: OR (95% CI) 0.90 (0.86-0.94), p=2.6 x 10(-6) for men and 0.77 (0.68-0.87), p=3.2 x 10(-5) for women, respectively for each 0.1mg/dl increase of bilirubin. These results indicate that it is rather decreased bilirubin levels in general than the changes in the genetic variation of this gene that increase the risk for CAD.
| S-EPMC2648823 | biostudies-literature
Project description:AIM: Omentin-1, a novel adipokine expressed in visceral adipose tissue, is negatively correlated with insulin resistance and obesity. Decreased omentin-1 expression has been found in many chronic inflammatory diseases. However, the role of omentin-1 in coronary artery disease (CAD) has not been elucidated. The aim of the present study was to determine whether serum concentration of omentin-1 was independently associated with CAD. METHODS: One hundred and fifty five patients with CAD were divided into two groups: acute coronary syndrome (ACS) and stable angina pectoris (SAP). A total of 52 healthy participants served as controls. Serum concentrations of omentin-1 and interleukin-6 (IL-6) were measured using ELISA. The association of omentin-1 with CAD and cardiovascular disease risk factors was evaluated. RESULTS: Serum omentin-1 levels were lower in patients with ACS or SAP compared with controls (ACS, 113.08±61.43 ng/mL; SAP, 155.41±66.89 ng/mL; control, 254.00±72.9 ng/mL; P<0.01). Patients with ACS also had lower serum concentrations of omentin-1 compared with patients with SAP (P<0.01). Serum concentration of omentin-1 was negatively correlated with body mass index (r=-0.17, P<0.05) and serum IL-6 concentration (r=-0.19, P<0.05). Furthermore, multiple logistic regression analysis showed that serum omentin-1 concentrations were independently correlated with CAD. CONCLUSION: The findings suggest that serum concentrations of omentin-1 are related to CAD.
| S-EPMC4003121 | biostudies-other
Project description:Matrix Gla protein (MGP) was originally isolated from bone but it is known to be expressed in several tissues including kidney, lung, heart, cartilage and vascular smooth muscle cells (VSMC) of the blood vessel wall. Since it inhibits calcification in subendothelial space of vessels thus, we evaluated the association of rs1800802(T > C) polymorphism and stenosis of the coronary artery.Cross-sectional case-control.One hundred eighty two subjects recruited on the basis of study protocol from who underwent coronary angiography. The controls (n=70) had normal coronary arteries (up to 5% stenosis). The patients (n=112) subdivided into three subgroups; single-vessel disease (SVD), two-vessel disease (2VD) and three-vessel disease (3VD) based on the number of stenosed coronary vessels (at least 50% stenosis). rs1800802 (T > C) polymorphism was determined by PCR-RFLP technique.Genotype distribution was not significant between control and patient groups. In addition, there were no significant differences between rs1800802 (T > C) frequency and gender (P=.092), and also patient subgroups (one-, two- and three vessel disease) (P=.840).We concluded that rs1800802 (T > C) polymorphism within the MGP promoter is not related to stenosis of the coronary artery.
| S-EPMC6078625 | biostudies-literature
Project description:BackgroundRecent studies have demonstrated that a molecular subtype of glioblastoma is characterized by overexpression of extracellular matrix (ECM)/mesenchymal components and shorter survival. Specifically, gene expression profiling studies revealed that matrix gla protein (MGP), whose function has traditionally been linked to inhibition of calcification of arteries and cartilage, is overexpressed in glioblastomas and associated with worse outcome.MethodsIn order to analyze the role of MGP in glioblastomas, we performed expression, migration and proliferation studies.ResultsReal-time PCR and ELISA assays confirmed overexpression of MGP in glioblastoma biopsy specimens and cell lines at mRNA and protein levels as compared to normal brain tissue. Immunohistochemistry verified positivity of glial tumor cells for MGP. RNAi-mediated knockdown of MGP in three glioma cell lines (U343MG, U373MG, H4) led to marked reduction of migration, as demonstrated by wound healing and transwell assays, while no effect on proliferation was seen.ConclusionOur data suggest that upregulation of MGP (and possibly other ECM-related components as well) results in unfavorable prognosis via increased migration.
| S-EPMC2739228 | biostudies-literature
Project description:The ability to ablate a gene in a given tissue by generating a conditional knockout (cKO) is crucial for determining its function in the targeted tissue. Such tissue-specific ablation is even more critical when the gene's conventional knockout (KO) is lethal, which precludes studying the consequences of its deletion in other tissues. Therefore, here we describe a successful strategy that generated a Matrix Gla floxed mouse (Mgp.floxed) by the CRISPR/Cas9 system, that subsequently allowed the generation of cKOs by local viral delivery of the Cre-recombinase enzyme. MGP is a well-established inhibitor of calcification gene, highly expressed in arteries' smooth muscle cells and chondrocytes. MGP is also one of the most abundant genes in the trabecular meshwork, the eye tissue responsible for maintenance of intraocular pressure (IOP) and development of Glaucoma. Our strategy entailed one-step injection of two gRNAs, Cas9 protein and a long-single-stranded-circular DNA donor vector (lsscDNA, 6.7 kb) containing two loxP sites in cis and 900-700 bp 5'/3' homology arms. Ocular intracameral injection of Mgp.floxed mice with a Cre-adenovirus, led to an Mgp.TMcKO mouse which developed elevated IOP. Our study discovered a new role for the Mgp gene as a keeper of physiological IOP in the eye.
| S-EPMC7596545 | biostudies-literature
Project description:ImportanceSerum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.ObjectiveTo evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization.Design, setting, and participantsThe analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis.ExposuresGenetic risk score based on genetic variants related to elevated serum calcium levels.Main outcomes and measuresCo-primary outcomes were the odds of CAD and myocardial infarction.ResultsAmong the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction.Conclusions and relevanceA genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.
| S-EPMC5817597 | biostudies-literature
Project description:ObjectiveMatrix gla protein (MGP) inhibits arterial and cartilaginous calcification. A threonine to alanine (Thr83Ala) polymorphism (codon 83) in MGP is associated with myocardial infarction and femoral artery calcification. We examined the association of the MGP Thr83Ala polymorphism with quantity and progression of coronary artery calcification (CAC), a noninvasive measure of subclinical coronary atherosclerosis.Methods and resultsIn 605 participants of the Epidemiology of Coronary Artery Calcification Study, generalized linear mixed models were fit to determine the association of MGP Thr83Ala with CAC quantity and progression. There was a significant additive relation between MGP Thr83Ala and CAC progression (P=0.001). In the fully adjusted model, every 1 Ala83 allele increase was associated with an estimated 1.9% (95% confidence interval, 0.7%-3.0%) per year since baseline larger increase in CAC quantity. A proxy single nucleotide polymorphism for MGP Thr83Ala (rs6488724) was similarly associated with CAC progression in an independent cohort from the Genetic Epidemiology Network of Arteriopathy (GENOA) study.ConclusionsIncreased risk of myocardial infarction associated with MGP ThrAla83 genotype observed elsewhere may be related to faster progression of subclinical coronary atherosclerosis. MGP genotype could be a potential candidate for identifying individuals at increased risk of atherosclerotic disease who would benefit from aggressive primary prevention strategies.
| S-EPMC3586431 | biostudies-literature
Project description:The prevalence of coronary artery disease (CAD) is increasing globally, supporting the need for the identification of novel biomarkers. Therefore in the present study, we have explored the association of SIL2A, SIL6R, STNFRI, STNFRII, and MMP9 in CAD patients. Twenty one patients with angiographically defined CAD with more than 50% occlusion, at least, in one coronary artery and twenty healthy subjects (n=20) without the history of cardiovascular symptoms were enrolled. Demographic and biochemical analysis (e.g. Total Cholesterol (TC), Triglyceride (TG), and HDL-C) were measured in all the subjects. The level of cytokines receptor (SIL2A, SIL6R, SIL6R, STNFRI, STNFRII, and matrix metallopeptidase 9 (MMP9) were evaluated. Our results showed the higher level of MMP9 in patients group compared to the control subjects, while no significant differences were detected for other cytokines. In particular the level of MMP9 was significantly (P=.015) increased from 181.16 ng/mL (95%CI: 112.1-199.2) to 192.0 ng/mL (95%CI: 181.5-265.2). Moreover, the sensitivity and specificity of MMP9 were 95.45% and 45%, respectively, as detected by receiver operating characteristic (ROC) curves. We demonstrate the significant correlation of MMP-9 with CAD with sensitivity of 95.45%, suggesting its role as a biomarker in CAD patients. Further studies in larger population - preferably multicenter setting - are warranted to explore the functional role of this marker in coronary artery disease.
| S-EPMC6817073 | biostudies-literature