The study of t-PA, u-PA and PAI-1 genes polymorphisms in patients with abdominal aortic aneurysm.
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ABSTRACT:
SUBMITTER: Oszajca K
PROVIDER: S-EPMC4013441 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since the first candidate gene studies were published 20 years ago, approximately 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. These studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, only when appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called contactin-3, which is located on chromosome 3p12.3. However, two follow-up studies could not replicate this association. Two other SNPs, which are located on chromosome 9p21 and 9q33, were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense ribonucleic acid that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute toward AAA pathogenesis.
| S-EPMC3058859 | biostudies-literature
Project description:Male gender and family history are risk factors for abdominal aortic aneurysm (AAA). We hypothesized that genes involved in sex hormones might be important in AAA. We investigated the association of aortic diameter with single-nucleotide polymorphisms (SNPs) in genes determining circulating sex hormones and their action. We genotyped 74 tagging SNPs across four genes (steroid 5α reductase, subfamily A, polypeptide 1 (SRD5A1), cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1), androgen receptor (AR) and estrogen receptor 2 (ESR2)) related to sex hormone production and action in 1711 men, 640 of whom had an AAA. One genotype was also assessed in an independent cohort of 782 men, of whom 513 had large AAAs. Associations were assessed adjusting for other risk factors for AAA. One SNP in CYP19A1 was strongly associated with aortic diameter. Subjects who had the rare homozygote genotype (TT) for CYP19A1g.49412370C>T (SNP ID rs1961177), had an increased aortic diameter (coefficient 5.058, SE 1.394, P=0.0003, under a recessive model). This SNP was not associated with aortic diameter in an independent cohort, which included patients with larger AAAs. Our findings do not support an important role of genetic polymorphisms in genes determining sex hormones in aortic dilatation in men. The association of one SNP in CYPA9A1 with small but not large AAA may suggest differences between AAA formation and progression. This SNP warrants further investigation in another large population, including patients with small AAAs.
| S-EPMC3062004 | biostudies-literature
Project description:Increased matrix metalloproteinase (MMP) 9 activity has been implicated in the formation of abdominal aortic aneurysm (AAA). The aim was to explore the association between potentially functional variants of the MMP-9 gene and AAA.The -1562C > T and -1811A > T variants of the MMP-9 gene were genotyped in 678 men with an AAA (at least 30 mm in diameter) and 659 control subjects (aortic diameter 19-22 mm) recruited from a population-based trial of screening for AAA. Levels of MMP-9 were measured in a random subset of 300 cases and 84 controls. The association between genetic variants (including haplotypes) and AAA was assessed by multivariable logistic regression.There was no association between the MMP-9-1562C > T (odds ratio (OR) 0.70 (95 per cent confidence interval (c.i.) 0.27 to 1.82)) or -1811A > T (OR 0.71 (95 per cent c.i. 0.28 to 1.85)) genotypes, or the most common haplotype (OR 0.81 (95 per cent c.i. 0.62 to 1.05)) and AAA. The serum MMP-9 concentration was higher in cases than controls, and in minor allele carriers in cases and controls, although the differences were not statistically significant.In this study, the genetic tendency to higher levels of circulating MMP-9 was not associated with AAA.
| S-EPMC2597005 | biostudies-literature
Project description:Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA.
| S-EPMC4495250 | biostudies-literature
Project description:Background:Abdominal aortic aneurysm (AAA) is the full thickness dilation of the abdominal aorta. However, few effective medical therapies are available. Thus, elucidating the molecular mechanism of AAA pathogenesis and exploring the potential molecular target of medical therapies for AAA is of vital importance. Methods:Three expression datasets (GSE7084, GSE47472 and GSE57691) were downloaded from the Gene Expression Omnibus (GEO). These datasets were merged and then normalized using the "sva" R package. Differential expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were conducted. We compared the co-expression patterns between AAA and normal conditions, and hub genes of each functional module were identified. DEGs were mapped to co-expression network under AAA condition and a DEG co-expression network was generated. Crucial genes were identified using molecular complex detection (MCODE) (a plugin in Cytoscape). Results:In our study, 6 and 10 gene modules were detected for the AAA and normal conditions, respectively, while 143 DEGs were screened. Compared to the normal condition, genes associated with immune response, inflammation and muscle contraction were clustered in three gene modules respectively under the AAA condition; the hub genes of the three modules were MAP4K1, NFIB and HPK1, respectively. A DEG co-expression network with 102 nodes and 303 edges was identified, and a hub gene cluster with 10 genes from the DEG co-expression network was detected. YIPF6, RABGAP1, ANKRD6, GPD1L, PGRMC2, HIGD1A, GMDS, MGP, SLC25A4 and FAM129A were in the cluster. The expression levels of these 10 genes showed potential diagnostic value. Conclusion:Based on WGCNA, we detected 6 modules under the AAA condition and 10 modules in the normal condition. Hub genes of each module and hub gene clusters of the DEG co-expression network were identified. These genes may act as potential targets for medical therapy and diagnostic biomarkers. Further studies are needed to elucidate the detailed biological function of these genes in the pathogenesis of AAA.
| S-EPMC6788446 | biostudies-literature
Project description:Approximately 13,000 people die of an abdominal aortic aneurysm (AAA) every year. This study aimed to identify the immune response-related genes that play important roles in AAA using bioinformatics approaches. We downloaded the GSE57691 and GSE98278 datasets related to AAA from the Gene Expression Omnibus database, which included 80 AAA and 10 normal vascular samples. CIBERSORT was used to analyze the samples and detect the infiltration of 22 types of immune cells and their differences and correlations. The principal component analysis showed significant differences in the infiltration of immune cells between normal vascular and AAA samples. High proportions of CD4+ T cells, activated mast cells, resting natural killer cells, and 12 other types of immune cells were found in normal vascular tissues, whereas high proportions of macrophages, CD8+ T cells, resting mast cells, and six other types of immune cells were found in AAA tissues. In the selected samples, we identified 39 upregulated (involved in growth factor activity, hormone receptor binding, and cytokine receptor activity) and 133 downregulated genes (involved in T cell activation, cell chemotaxis, and regulation of immune response mediators). The key differentially expressed immune response-related genes were screened using the STRING database and Cytoscape software. Two downregulated genes, PI3 and MAP2K1, and three upregulated genes, SSTR1, GPER1, and CCR10, were identified by constructing a protein-protein interaction network. Functional enrichment of the differentially expressed genes was analyzed, and the expression of the five key genes in AAA samples was verified using quantitative polymerase chain reaction, which revealed that MAP2K1 was downregulated in AAA, whereas SSTR1, GEPR1, and CCR10 were upregulated; there was no significant difference in PI3 expression. Our study shows that normal vascular and AAA samples can be distinguished via the infiltration of immune cells. Five genes, PI3, MAP2K1, SSTR1, GPER1, and CCR10, may play important roles in the development, diagnosis, and treatment of AAA.
| S-EPMC7758434 | biostudies-literature
Project description:Endovascular aneurysm repair (EVAR) has dramatically changed the management of abdominal aortic aneurysms (AAAs) as the number of open aneurysm repairs have declined over time. This report compares AAA-related demographics, operative data, complications, and mortality after treatment by open aneurysm repair or EVAR.We retrospectively reviewed 136 patients with AAAs who were treated over an 8-year time period with open aneurysm repair or EVAR.The mean age of the EVAR group was higher than that of the open repair group (p=0.001), and hospital mortality did not differ significantly between groups (p=0.360). However, overall survival was significantly lower in the EVAR group (p=0.033).Although EVAR is the primary treatment modality for elderly patients, it would be ideal to set slightly more stringent criteria within the anatomical guidelines contained in the instructions for use of the EVAR device when treating younger patients.
| S-EPMC5548202 | biostudies-other
Project description:PurposeAbdominal aortic aneurysm (AAA) is a critical disease. Most studies of AAA consider reoperation rate, complications, or mortality, but do not consider a patient's mental state. However, there is a possibility of interaction between AAA and depression in disease development and prognosis. We investigated the incidence and risk ratio of depression in patients with AAA using nationwide data.MethodsWe selected subjects from National Health Insurance System database who were diagnosed with AAA between 2009 and 2015 and survived at least 1 year after diagnosis or AAA surgery (n = 10,373). We determined the control group using propensity score matching by age and sex. The control group had about 3 times the number of subjects as the AAA cohort (n = 31,119).ResultsThe incidence of depression was 1.4 times higher in the AAA group than the control group. We further analyzed the incidence of depression in the AAA group according to treatment modalities (nonsurgical vs. surgical or nonsurgical vs. open surgical aneurysm repair vs. endovascular aneurysm repair) but found no significant difference among them. The incidence of depression was significantly higher in patients aged <65 years than in patients aged ≥65 years (hazard ratio, 1.539 vs. 1.270; P < 0.001).ConclusionThe incidence of depression was higher in the AAA group, with an especially high risk for depression in patients aged <65 years. The psychiatric status of patients with AAA should be carefully monitored for clinicians to intervene when appropriate.
| S-EPMC8564076 | biostudies-literature
Project description:Abdominal aortic aneurysm (AAA) is a multifactorial condition. The transforming growth factor beta (TGF-beta) pathway regulates vascular remodeling and mutations in its receptor genes, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysm (TAA). The TGF-beta pathway may be involved in aneurysm development in general. We performed an association study by analyzing all the common genetic variants in TGFBR1 and TGFBR2 using tag single nucleotide polymorphisms (SNPs) in a Dutch AAA case-control population in a two-stage genotyping approach. In stage 1, analyzing 376 cases and 648 controls, three of the four TGFBR1 SNPs and nine of the 28 TGFBR2 SNPs had a P<0.07. Genotyping of these SNPs in an independent cohort of 360 cases and 376 controls in stage 2 confirmed association (P<0.05) for the same allele of one SNP in TGFBR1 and two SNPs in TGFBR2. Joint analysis of the 736 cases and 1024 controls showed statistically significant associations of these SNPs, which sustained after proper correction for multiple testing (TGFBR1 rs1626340 OR 1.32 95% CI 1.11-1.56 P=0.001 and TGFBR2 rs1036095 OR 1.32 95% CI 1.12-1.54 P=0.001 and rs4522809 OR 1.28 95% CI 1.12-1.46 P=0.0004). We conclude that genetic variations in TGFBR1 and TGFBR2 associate with AAA in the Dutch population. This suggests that AAA may develop partly by similar defects as TAA, which in the future may provide novel therapeutic options.
| S-EPMC2987181 | biostudies-literature
Project description:PurposeTo evaluate the aortic neck anatomy in Korean patients with abdominal aortic aneurysms (AAAs).Materials and methodsWe examined computed tomography scans of 343 patients with AAAs (≥5.5 cm for men or ≥5 cm for women) between 2009 and 2018. Eligibility of neck anatomy for endovascular aneurysm repair (EVAR) was assessed with the standard instructions for use (IFU) (length ≥15 mm, suprarenal angulation (SRA) ≤45°, infrarenal angulation (IRA) ≤60°, and diameter 18-32 mm) and the extended IFU (length ≥10 mm, SRA ≤60°, IRA ≤75°, and diameter 17-32 mm).ResultsThere were 71 women (20.7%), and 61 patients (17.8%) with rupture. Women had smaller neck diameters (21.3 vs. 23.4 mm, P<0.001 for proximal neck; 22.2 vs. 24.5 mm, P<0.001 for distal neck), and higher angulations (51.5° vs. 37.8°, P<0.001 for SRA; 77.7° vs. 57.0°, P<0.001 for IRA) than men. However, the neck length was not significantly different. Patients with ruptured AAAs had shorter neck lengths (21.0 vs. 26.8 mm, P=0.005) than those with intact AAAs. However, the neck diameters and angulations were not significantly different. EVAR eligibility for standard and extended IFUs was found in 37.5% and 55.1% of men, and 11.3% and 25.4% of women (P<0.001 for both IFUs); neck anatomy was eligible in 34.0% of intact AAAs and 23.0% of ruptured AAAs (P=0.098).ConclusionA significant proportion of the Korean patients did not meet the IFU for EVAR, mainly due to the angulated neck. Women, and patients with ruptured AAAs, were less likely to meet the IFU criteria.
| S-EPMC7333089 | biostudies-literature