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1.
Gene ; 721: 144107, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31499127

RESUMO

BACKGROUND: Gene environment interactions leading to epigenetic alterations play pivotal role in the pathogenesis of Coronary Artery Disease (CAD). Altered DNA methylation is one such epigenetic factor that could lead to altered disease etiology. In this study, we comprehensively identified methylation sites in several genes that have been previously associated with young CAD patients. METHODS: The study population consisted of 42 healthy controls and 33 young CAD patients (age group <50 years). We performed targeted bisulfite sequencing of promoter as well as gene body regions of several genes in various pathways like cholesterol synthesis and metabolism, endothelial dysfunction, apoptosis, which are implicated in the development of CAD. RESULTS: We observed that the genes like GALNT2, HMGCR were hypermethylated in the promoter whereas LDLR gene promoter was hypomethylated indicating that intracellular LDL uptake was higher in CAD patients. Although APOA1 did not show significant change in methylation but APOC3 and APOA5 showed variation in methylation in promoter and exonic regions. Glucokinase (GCK) and endothelial nitric oxide synthase 3 (NOS3) were hyper methylated in the promoter. Genes involved in apoptosis (BAX/BCL2/AKT2) and inflammation (PHACTR1/LCK) also showed differential methylation between controls and CAD patients. A combined analysis of the methylated CpG sites using machine learning tool revealed 14 CpGs in 11 genes that could discriminate CAD cases from controls with over 93% accuracy. CONCLUSIONS: This study is unique because it highlights important gene methylation alterations which might predict the risk of young CAD in Indian population. Large scale studies in different populations would be important for validating our findings and understanding the epigenetic events associated with CAD.


Assuntos
Doença da Artéria Coronariana/metabolismo , Ilhas de CpG , Metilação de DNA , Análise de Sequência de DNA , Adulto , Apolipoproteínas/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Sulfitos/química
2.
Adv Clin Exp Med ; 28(9): 1243-1248, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31430072

RESUMO

BACKGROUND: FoxP3 is a marker of human T regulatory cells (Tregs), which are supposed to play an important role in the pathophysiology of atherosclerosis. Interleukin 10 (IL-10) is a cytokine with pleiotropic, immunoregulatory properties, produced mostly by Tregs and B regulatory cells. Due to their anti-inflammatory action, both Tregs and IL-10 are believed to inhibit plaque development and decrease atherosclerosis progression. The effect of hypolipidemic drugs - statins or ezetimibe - on FoxP3-positive Tregs and anti-inflammatory cytokines, such as IL-10, is still unclear. OBJECTIVES: The objective of the study was to investigate the effects of 3 different therapies of equivalent hypolipidemic activity: atorvastatin, rosuvastatin, and combination therapy of atorvastatin and ezetimibe on FoxP3-Tregs transcription factor and IL-10 mRNA expression in peripheral blood mononuclear cells (PBMCs) from patients with stable coronary artery disease (CAD). MATERIAL AND METHODS: Sixty-five patients with diagnosed CAD participated in the study. They were randomly assigned to 3 therapeutic groups: atorvastatin at a dose of 40 mg/day (A40 group); rosuvastatin 20 mg/day (R20 group); and atorvastatin 10 mg/day combined with ezetimibe 10 mg/day (A10+E10 group). After 1 month and 6 months of therapy, the mRNA expression for FoxP3 and IL-10 in PBMCs was evaluated using real-time polymerase chain reaction (RT-PCR) and lipid parameters. RESULTS: An improvement in lipid parameters was observed in each of the groups studied; however, hypolipidemic treatment did not induce any change in FoxP3 and IL-10 mRNA expression. After 6 months, an increase in FoxP3 mRNA expression was noted in A40 group as compared to R20 group. CONCLUSIONS: None of the therapies of equal hypolipidemic efficacy affected FoxP3 and IL-10 mRNA expression in patients with stable CAD.


Assuntos
Anticolesterolemiantes , Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Ezetimiba/uso terapêutico , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-10/metabolismo , Leucócitos Mononucleares , RNA Mensageiro
3.
Braz J Med Biol Res ; 52(8): e8309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31411246

RESUMO

This study aimed to detect the expression of the long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) and evaluate its correlation with disease risk, stenosis degree, inflammation, as well as overall survival (OS) in coronary artery disease (CAD) patients. A total of 230 patients who underwent diagnostic coronary angiography were consecutively recruited and assigned to CAD group (n=125) or control group (n=105) according to presence or absence of CAD. Gensini score was calculated to assess the severity of coronary artery damage. Plasma samples were collected and the expression ANRIL was detected in all participants. High-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, IL-8, IL-10, and IL-17 in CAD patients were measured and OS was calculated. The relative expression of ANRIL was higher in CAD patients compared to controls (P<0.001). Receiver operating characteristic disclosed that ANRIL could distinguish CAD patients from controls with an area under the curve of 0.789 (95%CI: 0.731-0.847). Spearman's rank correlation test revealed that expression of ANRIL was positively correlated with Gensini score (P=0.001), levels of hs-CRP (P=0.001), ESR (P=0.038), TNF-α (P=0.004), and IL-6 (P<0.001), while negatively correlated with IL-10 level (P=0.008) in CAD patients. Kaplan-Meier curve revealed that high expression of ANRIL was associated with shorter OS (P=0.013). In conclusion, circulating ANRIL presented a good diagnostic value for CAD, and its high expression was associated with increased stenosis degree, raised inflammation, and poor OS in CAD patients.


Assuntos
Doença da Artéria Coronariana/diagnóstico , RNA Longo não Codificante/genética , Idoso , Sedimentação Sanguínea , Proteína C-Reativa/análise , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Estenose Coronária/complicações , Citocinas/sangue , Feminino , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Análise de Sobrevida
4.
Genome Biol ; 20(1): 133, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31287004

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene expression, open chromatin region, and 3D interactions in resting and TNFα-treated human endothelial cells. RESULTS: We show that genetic variants associated with CAD and BP are enriched in open chromatin regions identified in endothelial cells. We identify physical loops by Hi-C and link open chromatin peaks that include CAD or BP SNPs with the promoters of genes expressed in endothelial cells. This analysis highlights 991 combinations of open chromatin regions and gene promoters that map to 38 CAD and 92 BP GWAS loci. We validate one CAD locus, by engineering a deletion of the TNFα-sensitive regulatory element using CRISPR/Cas9 and measure the effect on the expression of the novel CAD candidate gene AIDA. CONCLUSIONS: Our data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD and hypertension.


Assuntos
Doença da Artéria Coronariana/genética , Proteínas de Transferência de Fosfolipídeos/genética , Sistemas CRISPR-Cas , Células Endoteliais/metabolismo , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Elementos Reguladores de Transcrição , Transcriptoma
5.
Biomed Khim ; 65(3): 239-244, 2019 Apr.
Artigo em Russo | MEDLINE | ID: mdl-31258148

RESUMO

The purpose of the study was to investigate the features of expression and adiponectin content in the adipocyte culture of subcutaneous, epicardial, and perivascular adipose tissue and the effect of various doses of rosuvastatin on these processes. 29 patients with coronary artery disease were examined. Adipocytes were isolated from the samples of SAT, EAT and PVAT which were taken during coronary artery bypass surgery, followed by cultivation in the presence of rosuvastatin and evaluation of gene expression and adiponectin concentration. Adipocytes SAT, EAT and PVAT differed in the level of adiponectin secretion and expression of its gene. On day 1 of cultivation the expression of the adiponectin gene in the EAT was 2.3 times lower than in the PVAT. On day 2 of cultivation the expression of the adiponectin gene was reduced both in the EAT and the PVAT as compared to the SAT. When rosuvastatin was added at a concentration of 1 mmol/L, adiponectin gene expression in PVAT was higher than when rosuvastatin was added at a concentration of 5 mmol/L, in the adipocyte culture of SAT effect was opposite. Thus, the adipocytes of EZhT and, to a greater extent, PAS, can be a therapeutic target for statins in the case of the pathological activation of adipose tissue.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/metabolismo , Adipócitos/efeitos dos fármacos , Adiponectina/genética , Células Cultivadas , Doença da Artéria Coronariana/genética , Expressão Gênica , Humanos , Rosuvastatina Cálcica/farmacologia
6.
Rev Assoc Med Bras (1992) ; 65(6): 923-929, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31340327

RESUMO

OBJECTIVE: To investigate the association between genotype insertion or deletion polymorphism of the angiotensin-converting enzyme gene (ACE) and susceptibility to coronary artery disease (CAD) in Chinese Han population. METHODS: We conducted a comprehensive search for the OR value of contrast between the group of genotype insertion or deletion polymorphism of the ACE and the group of CAD as an effective index. A meta-analysis (Stata 12.0) was used to test the heterogeneity of the results, combine the values for effect, conduct sensitivity analysis, and basic evaluation. RESULTS: A total of 638 studies were found on the association between polymorphisms of the angiotensin-converting enzyme gene and CAD, of which 44 studies met the inclusion criteria. In total, our study included 5619 cases and 4865 controls. The heterogeneity test of each study (P < 0.001) was carried out using a random effect model. The OR value of DD/ID+II was 1.95, 95% confidence interval (95%CI) (1.66-2.29). The OR value of II/DI+DD was 0.63, 95%CI (0.55-0.72). The funnel figure is basically symmetrical and the results of the sensitivity analysis were stable. CONCLUSION: The DD genotype of the angiotensin converting enzyme gene may be a weaker risk factor for CAD in the Chinese Han population.


Assuntos
Doença da Artéria Coronariana/genética , Estudos de Associação Genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , China/etnologia , Doença da Artéria Coronariana/etnologia , Humanos , Fatores de Risco
7.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(7): 839-843, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31357808

RESUMO

Objective: To assess the casual effect of childhood obesity on adulthood coronary artery disease (CAD) using Mendelian randomization (MR) method. Methods: Data on BMI of children aged 2-10 years in 2015 were downloaded from Early Growth Genetics Consortium and Genetic Investigation of Anthropometric Traits Consortium. Twenty-seven genetic variants related to children's BMI were selected as instrumental variables (IVs), and the associations between IVs and CAD were extracted from a Meta-analysis of the genome-wide association study of CAD cases published in UK Biobank 2015. We used MR-Egger regression to test whether there was the pleiotropy of the selected SNPs. In the present MR methods, we conducted MR analyses by using mode-based estimate method as primary method for summary-level of associations to estimate the causal association between childhood obesity and CAD. Results: The intercept term estimated for CAD from MR-Egger method suggested that the selected SNPs don't exert pleiotropy with a 95%CI including the null (-0.008-0.018). In addition, we found evidence that support the effect of childhood obesity on CAD risk: a 1 s increase in children BMI (kg/m(2)), and the risk of suffering from CAD in adulthood increased by an average of 37% (OR=1.37, 95%CI: 1.09-1.72). Conclusion: This study provides a causal association between childhood obesity and CAD risk.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Obesidade Pediátrica/epidemiologia , Criança , Pré-Escolar , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Metanálise como Assunto , Obesidade Pediátrica/genética , Polimorfismo de Nucleotídeo Único
9.
DNA Cell Biol ; 38(8): 880-886, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237437

RESUMO

Interleukin-23 (IL-23) has been associated with atherosclerosis in both humans and animal models with contradictory results. This cytokine is conformed by an α p19 (encoded by IL-23A gene) and a ß p40 subunit (encoded by IL-12B gene). The aim of this study was to evaluate the association of two polymorphisms located within (rs11171806) or near (rs2066808) of the IL-23A gene with the presence of premature coronary artery disease (CAD) and with cardiometabolic parameters. The rs2066808 and rs11171806 polymorphisms were determined in 2249 Mexican individuals (1160 with premature CAD and 1089 healthy controls). Under recessive and codominant 2 models, adjusted by confounding variables, the rs2066808 polymorphism could increase the genetic risk of premature CAD (odds ratio [OR] = 4.567, 95% confidence interval [CI]: 1.03-20.24, Precessive = 0.046 and OR = 4.606, 95% CI: 1.039-20.43, Pcodominant2 = 0.044). The association of the polymorphisms with cardiovascular risk factors was evaluated separately in premature CAD patients and healthy controls. In patients, the rs2066808 polymorphism could decrease the genetic risk of hyperinsulinemia, insulin resistance, and hypoalphalipoproteinemia, and increase the genetic risk of hyperuricemia, whereas the rs11171806 polymorphism could decrease the genetic risk of hyperinsulinemia and insulin resistance. In healthy controls, the rs11171806 polymorphism could decrease the genetic risk of hyperinsulinemia. These findings suggest that the rs2066808 polymorphism located near the IL-23A gene could increase the genetic risk of premature CAD and both studied polymorphisms could be associated with some cardiometabolic parameters in premature CAD patients and in healthy controls.


Assuntos
Doença da Artéria Coronariana/genética , Subunidade p19 da Interleucina-23/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , México , Pessoa de Meia-Idade
10.
Gene ; 710: 324-332, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31173806

RESUMO

BACKGROUND: Periodontal disease (PD), a chronic inflammatory disorder mediated by progressive destruction of the oral cavity is one of the key factors for many systemic disorders including Coronary Artery Disease (CAD). The upregulation of CDKN2BAS, a long noncoding RNA gene expression in gingival epithelial cells and gingival fibroblasts of periodontitis shows a strong correlation between the severity of atherosclerosis and PD. Considering the crucial role of CDKN2BAS gene polymorphisms (rs496892 G > A and rs7865618 A > G) and its expression the present study sought to identify the possible association with the disease predisposition in South Indian population. METHODS: For the present case-control study a total of 200 subjects that include 100 PD-CAD patients and 100 controls were recruited with prior consent. Genomic DNA and RNA were extracted and utilized for genotyping via ARMS-PCR and PCR-RFLP, and expression using RT-PCR respectively. RESULTS: The results showed a significant association of both the polymorphisms with that of the disease predisposition. The wild type genotypes (GG: OR-0.37; p-0.001; & AA: OR-0.29; p-0.005) conferred protection against the disease, whereas, the heterozygotes (GA: OR-2.45; p-0.004 & AG: OR-3.41; p-0.0001) conferred risk towards the disease, suggesting the involvement of the variant allele in disease causation. These results were further confirmed by haplotype analysis among A-G block (two variant alleles at both loci) with 2.5 fold risk (OR = 2.49, 95% CI = 1.16-5.36, p = 0.02) and G-G block (single risk allele at rs7865618 locus) with 3-fold risk (OR-3.0; p-0.01) towards the disease, suggesting the dominant involvement of rs7865618 in the disease causation. Though the expression of the CDKN2BAS gene is more in patients than controls, the variant genotypes among patients were evaluated to be down-regulated than the other genotypes. CONCLUSION: The present study concludes that the two selected polymorphisms have significant involvement individually and in interaction with each other in the disease predisposition. The expression studies also suggest that the selected polymorphisms in the 9p21.3 locus affect the CDKN2BAS gene expression. However, the results obtained in the present study should be confirmed with large samples in other ethnic cohorts.


Assuntos
Doença da Artéria Coronariana/genética , Periodontite/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima
11.
PLoS Comput Biol ; 15(5): e1007052, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31075101

RESUMO

Protein domains are basic functional units of proteins. Many protein domains are pervasive among diverse biological processes, yet some are associated with specific pathways. Human complex diseases are generally viewed as pathway-level disorders. Therefore, we hypothesized that pathway-specific domains could be highly informative for human diseases. To test the hypothesis, we developed a network-based scoring scheme to quantify specificity of domain-pathway associations. We first generated domain profiles for human proteins, then constructed a co-pathway protein network based on the associations between domain profiles. Based on the score, we classified human protein domains into pathway-specific domains (PSDs) and non-specific domains (NSDs). We found that PSDs contained more pathogenic variants than NSDs. PSDs were also enriched for disease-associated mutations that disrupt protein-protein interactions (PPIs) and tend to have a moderate number of domain interactions. These results suggest that mutations in PSDs are likely to disrupt within-pathway PPIs, resulting in functional failure of pathways. Finally, we demonstrated the prediction capacity of PSDs for disease-associated genes with experimental validations in zebrafish. Taken together, the network-based quantitative method of modeling domain-pathway associations presented herein suggested underlying mechanisms of how protein domains associated with specific pathways influence mutational impacts on diseases via perturbations in within-pathway PPIs, and provided a novel genomic feature for interpreting genetic variants to facilitate the discovery of human disease genes.


Assuntos
Doença/etiologia , Domínios Proteicos , Mapas de Interação de Proteínas , Animais , Animais Geneticamente Modificados , Biologia Computacional , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença/genética , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Animais , Modelos Biológicos , Mutação , Polimorfismo de Nucleotídeo Único , Domínios Proteicos/genética , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Peixe-Zebra/genética
12.
Gene ; 710: 122-130, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31075415

RESUMO

PURPOSE: Coronary artery disease (CAD) is one of the most common causes of morbidity and mortality globally. This work aimed to investigate the specific modules and feature genes associated with CAD. METHODS: Three microarray datasets were downloaded from the Gene Expression Omnibus database, which included CAD and healthy samples. WGCNA was applied to identify highly preserved modules across the three datasets. MetaDE method was used to select differentially expressed genes (DEGs) with significant consistency. Protein-protein interaction (PPI) network was constructed using the overlapping genes amongst the DEGs with significant consistency and in the preserved modules. Moreover, a combined machine learning of support vector machine and recursive feature elimination was used to further investigate the feature genes and pathways. RESULTS: Nine highly preserved modules were detected in the WGCNA network, and 961 DEGs with significant consistency across the three datasets were selected using the metaDE method. A PPI network was constructed with the 158 overlapping genes. Ten genes were found to be involved in these KEGG pathways directly, including genes CD22, CD79B, CD81, CR1, IKBKE, MAP3K3, MAPK14, MMP9, NCF4, and SPP1. CONCLUSIONS: The present work might provide novel insight into the underlying molecular mechanism of CAD.


Assuntos
Biologia Computacional/métodos , Doença da Artéria Coronariana/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Mapas de Interação de Proteínas , Máquina de Vetores de Suporte
13.
Life Sci ; 231: 116510, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31141710

RESUMO

AIMS: Coronary artery disease (CAD) ranks the leading cause of death globally. Interferon-γ (IFN-γ) gene, along with long noncoding RNA (lncRNA) BRAF-activated noncoding RNA (BANCR), could coordinately function in the occurrence of CAD. We hypothesized that level of IFN-γ, genetic variants of IFN-γ and BANCR gene should be associated with the occurrence of CAD. MATERIALS AND METHODS: A case-control study was conducted in Chinese population. KEY FINDINGS: We found that serum level of IFN-γ in CAD cases was significantly higher than that in controls (P < 0.001). Compared with the first quartile, all of the second (OR: 1.87; 95% CIs: 1.33-2.62), the third (OR: 1.79; 95% CIs: 1.30-2.45), and the fourth (OR: 3.98; 95% CIs: 2.59-6.12) quartiles of serum level of IFN-γ were associated with increased risk of CAD (P < 0.05). We found IFN-γ gene (rs2069705 and rs2430561), and 2 variants in lncRNA BANCR (rs6559446 and rs79823312) could increase CAD susceptibility in allelic and dominant model, while IFN-γ rs2069705 and rs2430561, BANCR rs79823312 were also associated with CAD risk in additive model. IFN-γ rs2069705 and rs2430561 were associated with higher level of serum IFN-γ in CAD patients (P < 0.001). SIGNIFICANCE: This study confirmed the crucial role of IFN-γ and lncRNA BANCR in the occurrence of CAD, and might serve as the biomarkers of CAD screening and prevention.


Assuntos
Doença da Artéria Coronariana/genética , Interferon gama/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Autofagia , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Frequência do Gene , Humanos , Interferon gama/sangue , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , RNA Longo não Codificante/metabolismo
14.
Drug Discov Ther ; 13(2): 80-88, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080207

RESUMO

Numerous published studies have investigated the relationship between the paraoxonase 1 (PON1) gene Q192R (rs662) polymorphism and the risk of coronary artery disease (CAD) in type 2 diabetes mellitus (T2DM) patients. However, the results are still conflicting and inconclusive. Potentially eligible articles were searched for in related databases. Odds ratios (OR) with 95% confidence intervals (CI) were used to estimate the associations. Subgroup analysis was performed based on ethnicity. Ten case-control studies were included. A significant increase in the susceptibility for CAD in T2DM patients was found in the allelic model (OR = 1.49, p < 0.001), homozygote model (OR = 2.47, p < 0.001), heterozygote model (OR = 1.47, p < 0.001), dominant model (OR = 1.64, p < 0.001), and recessive model (OR = 1.74, p = 0.001). In subgroup analysis by ethnicity, a significant increase susceptibility was found in Asian populations in the allelic model (OR = 1.39, p = 0.001), homozygote model (OR = 2.15, p = 0.002), heterozygote model (OR = 1.37, p = 0.006), recessive model (OR = 1.65, p = 0.012), and dominant model (OR = 1.54, p < 0.001). A similar significant increase in susceptibility was found in Caucasian populations in the allelic model (OR = 1.75, p = 0.002), homozygote model (OR = 3.39, p = 0.002), recessive model (OR = 1.98, p = 0.030), heterozygote model (OR = 1.64, p = 0.001), and dominant model (OR = 1.83, p < 0.001). The results suggest that the PON1 Q192R polymorphism is associated with a significantly increased risk of CAD in T2DM patients in both Asian and Caucasian populations.


Assuntos
Arildialquilfosfatase/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/complicações , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Razão de Chances
15.
Gene ; 708: 1-9, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31082501

RESUMO

OBJECTIVES: Toll-like receptor 4 (TLR4) is known to be involved in the innate immunity and inflammatory responses that plays a crucial role in the pathogenesis of coronary artery disease (CAD). This study aimed to examine the potential relationship of TLR4 polymorphisms and serum TLR4 protein levels and the risk of CAD in the ethnic Zhuang population of China. METHODS: 1171 serum samples were collected from Zhuang patients, including 556 CAD cases (≥50% luminal stenosis of any coronary vessel) and 615 normal healthy controls (subjects with no luminal stenosis in coronary arteries). Detection of TLR4 polymorphisms was by single base extension polymerase chain reaction (Snapshot PCR) and DNA sequencing (rs11536879A/G and rs11536889G/C) gene sequence in all subjects. Serum TLR4 protein concentrations was measured by ELISA. RESULTS: There are significant differences in the allele and genotype frequencies of TLR4 gene rs11536889 between Chinese Zhuang CAD patients and controls, especially in the males. Male carriers of rs11536879 andrs11536889 variant alleles show an increased risk of CAD compared to non-carriers. Serum TLR4 protein levels of CAD patients are higher than controls and the levels tended to increase with the number of coronary artery lesions. Serum TLR4 protein levels of CAD patients showed no correlation with rs11536879 and rs11536889 polymorphisms. CONCLUSIONS: The rs11536879 and rs11536889 polymorphisms of TLR4 gene and serum TLR4 protein levels may contribute to the occurrence and development of CAD. However, the rs11536879 and rs11536889 polymorphisms have no significant effects on the expression of serum TLR4 protein in Zhuang patients with CAD.


Assuntos
Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Receptor 4 Toll-Like/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Doença da Artéria Coronariana/sangue , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Receptor 4 Toll-Like/sangue
16.
Indian Heart J ; 71(1): 60-64, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31000184

RESUMO

BACKGROUND: The cytochrome P-450 2J2 (CYP2J2) is known to be one of the major enzymes of epoxygenase pathway of arachidonic acid in extrahepatic tissues, which produces series of regioisomeric cis-epoxyeicosatrienoic acids (EETs) such as 5,6-, 8,9-, 11,12-, and 14,15-EETs. In the present study, we analyzed the impact of a genetic variant in CYP2J2 on coronary artery disease (CAD) in the Telangana region of Indian population. MATERIAL AND METHODS: The case-control study consisted of 100 CAD cases and 110 healthy controls. The deoxyribonucleic acid was extracted using the salting out method. Genotyping and gene expression was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time-PCR methods. RESULTS: In the present study, the percentage of smokers, alcoholics, hypertensive patients, and diabetics was high. Increase in fasting glucose, urea, creatinine, fasting triglycerides, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), total cholesterol/high-density lipoprotein (TC/HDL), LDL/HDL, homocysteine, and C-reactive protein levels were significantly higher in patients with CAD than in controls (p < 0.001). CYP2J2 G-50T was associated with CAD (p = 0.04). The mRNA expression of CYP2J2 showed altered gene expression in this study among CAD patients in comparison with control (p = 0.01). CONCLUSIONS: A functionally relevant polymorphism of the CYP2J2 gene was independently associated with an increased risk of CAD.


Assuntos
Doença da Artéria Coronariana/genética , Sistema Enzimático do Citocromo P-450/genética , DNA/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Adulto , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/epidemiologia , Sistema Enzimático do Citocromo P-450/biossíntese , Feminino , Seguimentos , Testes Genéticos , Genótipo , Humanos , Incidência , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Fatores de Risco
17.
In Vivo ; 33(3): 787-792, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31028198

RESUMO

BACKGROUND/AIM: Cholesterol ester transfer protein (CETP) is responsible for the transformation of high density lipoprotein (HDL) to low density lipoprotein (LDL) and is a risk factor for atherosclerosis. Our study investigated the association of the rs5883 CETP gene polymorphism with HDL and LDL levels, in 45 coronary artery disease patients and 45 control patients. MATERIALS AND METHODS: CETP gene polymorphism was detected using Real Time-Polymerase Chain Reaction (RT-PCR). Lipoprotein levels were measured using Quantimetrix system. RESULTS: There were lack of associaition regarding CETP polymorphism in atherosclerosis and HDL and LDL levels (p>0.05) BMI was higher among coronary artery disease patients (CADP) compared to the control group (28.97±6.38, 26.52±4.39 respectively, p<0.03). Frequency of CADP (82.6 %, n=19) who were taking treatment was higher (17.4 %, n=4) (p<0.00). The frequencies of hypertension and type-2 diabetes were higher among CADP (p<0.00). Families of CADP have more CADP (p<0.02). Small HDL particle levels were higher in the control group (p<0.00). CONCLUSION: In Turkey, BMI, and frequencies of hypertension and type-2 diabetes were higher among CADP than among healthy controls. Furthermore, the genotypes of the rs5883 CETP gene polymorphism did not differ between CADP and healthy controls.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Comorbidade , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Diabetes Res Clin Pract ; 151: 39-45, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30935928

RESUMO

AIMS: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder and its prevalence is rapidly increasing worldwide. Patients with T2DM suffer from an increased risk of vascular complications. Of these, the development of coronary artery disease (CAD) causes the most mortality in patients with T2DM, however, its underlying molecular mechanisms are not fully understood. Nutrient sensing pathways which play a key role in sensing cellular energy and nutrients levels are reported to dysregulated in metabolic disease like T2DM. The aim of this study was to investigate the expression levels of nutrient sensing genes including SIRT1, PRKAB1, PRKAB2 and mTOR in CAD+ versus CAD-T2DM patients. METHODS: Sixty-five people with T2DM who referred to Tehran heart center were participated in this study. Based on coronary angiography data these individuals were classified into two groups: CAD+ T2DM (n = 34) and CAD-T2DM (n = 31). Peripheral blood mononuclear cells were isolated from these patients and the expression levels of genes were evaluated by RT-qPCR. RESULTS: Significant down-regulations of the SIRT1 (3.1-fold, p = 0.0013) and PRKAB1 (3.5-fold, p = 0.0001) mRNA expression were observed in CAD+ T2DM group in comparison with CAD-T2DM patients. Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve was 0.8529 (p = 0.0001) and 0.7078 (p = 0.004) for PRKAB1 and SIRT1 respectively. CONCLUSION: Our results suggest that the dysregulation of genes involved in nutrient sensing pathway may be associated with the pathogenesis of CAD in patients with T2DM. Furthermore, the expression levels of these genes could be consider as potential biomarkers.


Assuntos
Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Nutrientes/sangue , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade
19.
J Cardiovasc Comput Tomogr ; 13(3): 21-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30935842

RESUMO

BACKGROUND: The Society of Cardiovascular Computed Tomography (SCCT) recommends consideration of coronary artery calcium (CAC) scoring among individuals with a family history (FH) of coronary heart disease (CHD) and atherosclerotic cardiovascular disease (ASCVD) risk <5%. No dedicated study has examined the prognostic significance of CAC scoring among this population. METHODS: The CAC Consortium is a multi-center observational cohort study from four clinical centers linked to long-term follow-up for cause-specific mortality. All CAC scans were physician referred and performed in patients without a history of CHD. Our analysis includes 14,169 patients with ASCVD scores <5% and self-reported FH of CHD. RESULTS: This cohort had a mean age of 48.1 (SD 7.4), was 91.3% white, 47.4% female, had an average ASCVD score of 2.3% (SD 1.3), and 59.4% had a CAC = 0. The event rate for all-cause mortality was 1.2 per 1000 person-years, 0.3 per 1000 person-years for CVD-specific mortality, and 0.2 per 1000 person-years for CHD-specific mortality. In multivariable Cox proportional hazard models, those with CAC>100 had a 2.2 (95% CI 1.5-3.3) higher risk of all-cause mortality, 4.3 (95% CI 1.9-9.5) times higher risk of CVD-specific mortality, and a 10.4 (95% CI 3.2-33.7) times higher risk of CHD-specific mortality compared to individuals with CAC = 0. The NNS to detect CAC >100 in this sample was 9. CONCLUSION: In otherwise low risk patients with FH of CHD, CAC>100 were associated with increased risk of all-cause and CHD mortality with event rates in a range that may benefit with preventive pharmacotherapy. These data strongly support new SCCT recommendations regarding testing of patients with a family history of CHD.


Assuntos
Angiografia por Tomografia Computadorizada/normas , Angiografia Coronária/normas , Doença da Artéria Coronariana/diagnóstico por imagem , Guias de Prática Clínica como Assunto/normas , Calcificação Vascular/diagnóstico por imagem , Adulto , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Bases de Dados Factuais , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Estados Unidos , Calcificação Vascular/genética , Calcificação Vascular/mortalidade , Calcificação Vascular/terapia
20.
Nat Commun ; 10(1): 1941, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028273

RESUMO

Mendelian randomization (MR) has emerged as a major tool for the investigation of causal relationship among traits, utilizing results from large-scale genome-wide association studies. Bias due to horizontal pleiotropy, however, remains a major concern. We propose a novel approach for robust and efficient MR analysis using large number of genetic instruments, based on a novel spike-detection algorithm under a normal-mixture model for underlying effect-size distributions. Simulations show that the new method, MRMix, provides nearly unbiased or/and less biased estimates of causal effects compared to alternative methods and can achieve higher efficiency than comparably robust estimators. Application of MRMix to publicly available datasets leads to notable observations, including identification of causal effects of BMI and age-at-menarche on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI on the risk of major depressive disorder.


Assuntos
Algoritmos , Neoplasias da Mama/genética , Doença da Artéria Coronariana/genética , Transtorno Depressivo Maior/genética , Genoma Humano , Análise da Randomização Mendeliana/estatística & dados numéricos , Fatores Etários , Índice de Massa Corporal , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etiologia , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Conjuntos de Dados como Assunto , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Menarca/sangue , Menarca/genética , Característica Quantitativa Herdável , Fatores de Risco , Triglicerídeos/sangue
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