Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.715
Filtrar
1.
Medicine (Baltimore) ; 98(42): e17106, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626081

RESUMO

BACKGROUND: Many studies investigated the association between miR-146a rs2910164 polymorphisms and risk of ischemic cardio-cerebrovascular diseases. However, the results were inconsistent. METHODS: We searched the PubMed, EMBASE, Cochrane library, Web of Science, Chinese National Knowledge Infrastructure, VIP, and Wanfang databases for appropriate studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations. Heterogeneity, sensitivity, and publication bias were conducted to measure the robustness of our findings.All analyses were based on previous published studies, thus, no ethical approval and patient consent are required. RESULTS: We conducted a meta-analysis to evaluate the relationship between miR-146a rs2910164 polymorphisms and risk of ischemic cardio-cerebrovascular diseases. A total of 26 related studies involving 11,602 cases and 14,016 controls were identified and included in our meta-analysis. After considering the heterogeneity of the global analysis, we inferred that rs2910164 polymorphisms were associated with a lower risk of coronary heart disease (CHD) significantly in all genetic models. In addition, it was also found that the miR-146a rs2910164 polymorphisms were associated with the low risk of ischemic cardio-cerebrovascular diseases in large sample size subgroup analysis. CONCLUSION: These results indicate that miR-146a rs2910164 polymorphisms were significantly associated with a lower risk of ischemic cardio-cerebrovascular. The miR-146a rs29101164 might be recommended as a predictor for susceptibility of ischemic cardio-cerebrovascular diseases.


Assuntos
Transtornos Cerebrovasculares/genética , Doença das Coronárias/genética , Predisposição Genética para Doença , MicroRNAs/genética , Humanos , Isquemia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
2.
Artigo em Inglês | MEDLINE | ID: mdl-31140911

RESUMO

Background: Coronary heart disease (CHD) is a chronic inflammatory disease, which is still regarded as a major cause of morbidity and mortality worldwide. Several studies have suggested that polymorphisms in cytokine genes are associated with the pathogenesis of CHD. The genotype distribution of Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) genes polymorphisms have been shown to be different in various ethnic populations. This study was aimed to investigate the association of TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms with risk of CHD in an Iranian population. Methods: A total of 187 unrelated subjects comprised 96 CHD patients and 91 healthy controls were enrolled in this cross-sectional study. The TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms were genotyped using amplification refractory mutation system-PCR (ARMS-PCR). The chi-square and logistic regression tests were used to calculate the odds ratios (ORs) as a measure of differences in genotype frequencies. Results: A significant differences in the allelic and genotypic distribution of TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms was found between CHD patients and healthy controls (P = 0.017, P = 0.011, P = 0.006 and P = 0.002, respectively). Logistic regression analyses were also revealed statistically significant risk for CHD with respect to TNF-α-308 A and IFN-γ + 874 T carriers either in crude or after adjustment for potential confounders (P = 0.003 and P = 0.006, respectively). Conclusion: This study provides strong evidence supporting the association of TNF-α-308G/A and IFN-γ + 874T/A polymorphisms with the increased risk of CHD. Therefore, these two cytokine polymorphisms may play a role in predisposition to coronary heart disease.


Assuntos
Doença das Coronárias/genética , Interferon gama/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Estudos de Casos e Controles , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético
3.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(4): 434-438, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31109416

RESUMO

OBJECTIVE: To explore the biological function of intercellular adhesion molecule-1 (ICAM-1) gene in coronary heart disease (CHD) and to establish a primary regulatory network mediated by ICAM-1 gene. METHODS: The databases were searched from January 1st 2006 to December 31st 2018, including Wanfang, CNKI, VIP, Google scholar and PubMed databases for published researches on clinical study of CHD gene ICAM-1. The experimental group was CHD patients, and the control group was healthy people. Meta-analysis was employed to analyze the relationship between ICAM-1 gene and CHD. Gene Ontology (GO) and KEGG Pathway database were employed to conduct function annotation and pathway analysis. RESULTS: A total of 8 papers were enrolled into this analysis, Meta-analysis showed that the level of ICAM-1 in the experimental group was significantly higher than that in the control group [mean difference (MD) = 15.29, 95% confidence interval (95%CI) = 10.95-19.62, P < 0.000 01], surface ICAM-1 was significantly related with CHD. The GO analysis results showed that ICAM-1 molecular function mainly involved virus receptor activity, receptor activity, transmembrane signal receptor activity, protein binding, etc.; cell components mainly involve plasma membrane integral components, immune synapses, plasma membrane, etc.; biological processes mainly involve the positive regulation of cell adhesion, leukocyte adhesion, leukocyte migration and leukocyte adhesion, etc. A primary CHD regulatory network mediated by ICAM-1 gene was established based on KEGG Pathway database, and ICAM-1 was mainly expressed in endothelial cells, and further regulated the occurrence and development of CHD by promoting the proliferation of leukocytes. CONCLUSIONS: ICAM-1 may regulate the occurrence and development of CHD by regulating the related biological processes of leukocytes. The successful establishment of the ICAM-1 mediated CHD regulatory network can lay a theoretical foundation for further exploring the specific regulatory role of ICAM-1 and other related genes in CHD occurrence.


Assuntos
Doença das Coronárias/genética , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/fisiologia , Fenômenos Biológicos , Doença das Coronárias/fisiopatologia , Redes Reguladoras de Genes , Humanos
4.
Med Sci Monit ; 25: 2633-2639, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30968846

RESUMO

BACKGROUND This study investigated the expression of the BCL2 and BAX mRNA, inflammatory cytokines, interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-alpha), and cardiac function in patients with chronic heart failure (CHF). The New York Heart Association (NYHA) Functional Classification and measurement of the left ventricular ejection fraction (LVEF) evaluated cardiac function. MATERIAL AND METHODS Patients with CHF (n=60) due to coronary heart disease, hypertensive heart disease, and cardiomyopathy, and healthy controls (n=30) were studied. Enzyme-linked immunosorbent assay (ELISA) measured serum levels of IL-1ß, IL-6, and TNF-alpha. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected mRNA expression of BCL2 and BAX in peripheral blood mononuclear cells (PBMCs). Color Doppler ultrasound measured the LVEF, and the NYHA classification of CHF was used. RESULTS In patients with CHF, levels of IL-1ß, IL-6 and TNF-alpha, and mRNA expression of BAX were significantly increased compared with the control group (p<0.01); BCL2 mRNA level was significantly lower (p<0.01). There were no significant differences in the expression levels of inflammatory cytokines, or BCL2 or BAX mRNA in patients with CHF due to coronary heart disease, hypertensive heart disease, or cardiomyopathy. Expression levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were significantly associated with the degree of CHF. Cardiac function was negatively correlated with LVEF (p<0.05). Expression levels of BCL2 mRNA level were negatively correlated with cardiac function (p<0.05), and positively correlated with LVEF (p<0.05). CONCLUSIONS Levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were negatively correlated with cardiac function, and BCL2 mRNA expression was positively associated with CHF.


Assuntos
Citocinas/sangue , Regulação da Expressão Gênica , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Mediadores da Inflamação/sangue , Leucócitos Mononucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Idoso , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Doença Crônica , Doença das Coronárias/sangue , Doença das Coronárias/genética , Doença das Coronárias/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Volume Sistólico , Proteína X Associada a bcl-2/sangue
5.
PLoS Genet ; 15(4): e1008009, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951530

RESUMO

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial , Fenótipo , Algoritmos , Glicemia/efeitos dos fármacos , Glicemia/genética , Análise por Conglomerados , Simulação por Computador , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Transtorno Depressivo Maior/classificação , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Estado Pré-Diabético/genética , Locos de Características Quantitativas
6.
Angiology ; 70(8): 726-736, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30871330

RESUMO

Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder predisposing affected individuals to lifelong low-density lipoprotein cholesterol (LDL-C) elevation and coronary heart disease. However, whether HeFH increases the risk of peripheral arterial disease (PAD) and ischemic stroke is undetermined. We examined associations between HeFH and these outcomes in a comprehensive systematic review and meta-analysis. We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, and PubMed (for ahead-of-print publications) for relevant English-language studies. Maximally adjusted risk estimates were pooled under random- and fixed-effects meta-analysis to derive odds ratios (ORs) and 95% confidence intervals (CIs). We included 6 studies representing 183 388 participants. Heterozygnous familial hypercholesterolemia was associated with a higher risk of PAD (OR: 3.59 [95% CI: 1.30-9.89]). This trend was nonsignificantly preserved (OR: 2.96 [95% CI: 0.68-12.88]) in sensitivity analyses of genetically defined HeFH. Genetic HeFH was not associated with increased ischemic stroke risk (OR: 0.76 [95% CI: 0.37-1.58]) although possessing an LDL-C >4.9 mmol/L (190 mg/dL) was (OR: 1.42 [95% CI: 1.06-1.89]). We found clinical and genetic diagnoses of HeFH to be associated with increased PAD risk. Genetically confirmed HeFH may not confer an increased risk of ischemic stroke. Modest associations may exist between LDL-C and ischemic stroke risk in HeFH.


Assuntos
Isquemia Encefálica/genética , Doença das Coronárias/genética , Hipercolesterolemia/genética , Doença Arterial Periférica/genética , Anticolesterolemiantes/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Doença das Coronárias/complicações , Doença das Coronárias/tratamento farmacológico , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Doença Arterial Periférica/complicações , Doença Arterial Periférica/tratamento farmacológico , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética
7.
Nat Commun ; 10(1): 1060, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837465

RESUMO

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Glicina/sangue , Hiperinsulinismo/genética , Redes e Vias Metabólicas/genética , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glicina/metabolismo , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/epidemiologia , Incidência , Polimorfismo de Nucleotídeo Único
8.
Curr Med Sci ; 39(1): 44-51, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30868490

RESUMO

This study sought to explore the relationship between cytochrome P450 2C19 (CYP2C19) *2/*3 polymorphisms and the development of coronary heart disease (CHD), and to evaluate the influence of the single nucleotide polymorphisms (SNPs) on the occurrence of adverse clinical events in CHD patients. A total of 231 consecutive patients candidate for percutaneous coronary intervention genotyped for CYP2C19*2 (681G>A) and *3 (636G>A) polymorphisms were enrolled. The adverse clinical events were recorded during a follow-up period of 14 months. The incidence of CHD, according to coronary angiography, was significantly higher (P=0.025) in CYP2C19*2 carriers group. Stepwise binary logistic regression analysis revealed that among factors that potentially influenced the presence of CHD (age>60 years, gender, BMI, etc.), CYP2C19*2 carriers (OR 1.94, 95% CI: 1.08-3.50, P=0.028) and male gender (OR 2.74, 95% CI: 1.58-4.76, P=0.001) were independent predictors, which were associated with the presence of CHD. The follow-up results showed that the incidence of adverse cardiovascular events within 14 months of discharge was significantly higher in the CYP2C19*2 carriers than in the non-carriers (21.6% vs. 6.3%, P=0.019). The results of the multivariate Cox proportional hazards model showed that CYP2C19*2 loss-of-function was the only independent factor which predicted the coronary events during the follow-up period of 14 months (OR=3.65, 95% CI 1.09-12.25, P=0.036). The adverse impact of CYP2C19*2 polymorphisms was found not only in the risk of the presence of CHD, but also in the adverse cardiovascular events in CHD patients during the follow-up period of 14 months. However the same influence was not found in CYP2C19*3 mutation in Chinese Han population.


Assuntos
Doença das Coronárias/genética , Doença das Coronárias/cirurgia , Citocromo P-450 CYP2C19/genética , Estudos de Associação Genética/métodos , Fatores Etários , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
9.
Diabetes ; 68(3): 479-489, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30787070

RESUMO

The past decade has witnessed an exponential increase in our ability to search the genome for genetic factors predisposing to cardiovascular disease (CVD) and in particular coronary heart disease (CHD). Identifying these genes could lead to the development of innovative strategies to prevent the cardiovascular complications of diabetes by allowing us to 1) create predictive algorithms for the identification of patients at especially high risk of CVD so that these individuals can undergo preventive interventions early in the natural history of the disease; 2) discover as yet unknown disease pathways linking diabetes to atherosclerosis, which can be used as targets for the development of new CVD-preventing drugs specifically directed at subjects with diabetes; and 3) devise personalized programs increasing the cost-effectiveness of preventive interventions by tailoring them to the genetic background of each patient. Substantial progress has been made in each of these three areas as exemplified by the recent development of a CHD genetic risk score improving CHD prediction among subjects with type 2 diabetes, the discovery of a diabetes-specific CHD locus on 1q25 pointing to glutamine synthase (GLUL) and the γ-glutamyl cycle as key regulators of CHD risk in diabetes, and the identification of two genetic loci allowing the selection of patients with type 2 diabetes who may especially benefit from intensive glycemic control. Translating these discoveries into clinical practice will not be without challenges, but the potential rewards, from the perspective of public health as well as that of persons with diabetes, make this goal worth pursuing.


Assuntos
Doenças Cardiovasculares/genética , Doença das Coronárias/genética , Diabetes Mellitus/genética , Algoritmos , Animais , Predisposição Genética para Doença/genética , Humanos
10.
Mol Med Rep ; 19(4): 2527-2536, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720076

RESUMO

Coronary heart disease (CHD) is a major cause of morbidity and mortality and an important public health problem globally, but the mechanism of CHD is still complex and unclear. The purpose of the current study was to explore the mechanism underlying CHD using high­throughput technology. The study participants were patients with coronary angiography (CAG)­proven severity of coronary artery stenosis. Patients were divided into control and test group based on specific inclusion criteria, and data were collected regarding the results of routine inspection and the Gensini score (GS). We explored the mechanism underlying CHD with high­throughput integration of circular RNA (circRNA)­microRNA (miRNA) data. Through the expression of circRNA­miRNA, we discovered a total of 110 circRNAs to be differentially expressed in the two groups. Of these, 73 were upregulated and 37 downregulated in the CHD (fold ≥2.0 and P<0.05). Among 18 miRNAs, 13 were upregulated and 5 were downregulated in the CHD group (fold ≥2.0 and P<0.05). Enrichment analysis showed that circRNAs participate in a variety of disease development processes, biological processes, molecular functions, cellular components, and pathways (P<0.05). The mechanism underlying CHD may be closely related to up­ or downregulated circRNA and miRNA and co­expression of circRNA­miRNA specifically involved regulate multiple pathways and multiple cellular and molecular biological processes.


Assuntos
Doença das Coronárias/genética , MicroRNAs , Análise de Sequência com Séries de Oligonucleotídeos , RNA , Adulto , Idoso , Biologia Computacional/métodos , Doença das Coronárias/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Pessoa de Meia-Idade , Mapas de Interação de Proteínas , Interferência de RNA , Transcriptoma
11.
PLoS One ; 14(2): e0211690, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30726294

RESUMO

BACKGROUND: The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. METHODS: 1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. RESULTS: Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. CONCLUSIONS: Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research.


Assuntos
Doença das Coronárias/genética , Intervenção Coronária Percutânea/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/cirurgia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade
12.
Gene ; 698: 34-40, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30802538

RESUMO

MicroRNA-499 (miR-499) rs3746444 polymorphism has been associated with the risk of coronary heart disease (CHD). However, results from several studies are inconsistent. This meta-analysis aimed to further investigate the possible association between miR-499 rs3746444 polymorphism and CHD risk. A total of 9 case-control studies included 5063 CHD cases and 4603 healthy subjects. The A allele at rs374644 was associated with significantly decreased CHD risk in the total population according to the allelic model (OR = 0.80, 95% CI = 0.68-0.93, P = 0.005), homozygous model (OR = 0.52, 95% CI = 0.39-0.71, P < 0.001) and heterozygous model (OR = 0.57, 95% CI = 0.43-0.77, P < 0.001). A similar trend was found specifically in Asian and Chinese populations. In contrast, the wild-type GG genotype at rs374644 was associated with significantly increased CHD risk in the total population, according to the dominant model (OR = 1.83, 95% CI = 1.39-2.42, P < 0.001), and a similar trend was found in Asian and Chinese populations. These results indicate that in the total population, as well as in Asian and Chinese populations, the wild-type GG genotype at rs374644 may be related to increased susceptibility to CHD, while the A allele may be protective against CHD.


Assuntos
Doença das Coronárias/genética , MicroRNAs/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
13.
PLoS One ; 14(1): e0210010, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30645616

RESUMO

BACKGROUND: The health economic evidence about the value and optimal targeting of genetic testing in the prevention of coronary heart disease (CHD) events has remained limited and ambiguous. The objective of this study is to optimize the population-level use and targeting of genetic testing alongside traditional risk factors in the prevention of CHD events and, thereby, to assess the cost-benefit of genetic testing. METHODS AND FINDINGS: We compare several strategies for using traditional and genetic testing in the prevention of CHD through statin therapy. The targeting of tests to different patient segments within these strategies is optimized by using a decision-analytic model, in which a patient's estimated risk of CHD is updated based on test results using Bayesian methods. We adopt the perspective of healthcare sector. The data for the model is exceptionally wide and combined from national healthcare registers, the Finnish Institute for Molecular Medicine, and published literature. Our results suggest that targeting genetic testing in an optimal way to those patients about which traditional risk factors do not provide sufficiently accurate information results in the highest expected net benefit. In particular, compared to the use of traditional risk factors only, the optimal use of genetic testing would decrease the expected costs of an average patient aged 45 years or more by 2.54€ in a 10-year follow-up period while maintaining the level of the expected health outcome. Thus, genetic testing is found to be a part of a cost-beneficial testing strategy alongside traditional risk factors. This conclusion is robust to reasonable changes in model inputs. CONCLUSIONS: If targeted optimally, the use of genetic testing alongside traditional risk factors is cost-beneficial in the prevention of CHD.


Assuntos
Doença das Coronárias/genética , Doença das Coronárias/prevenção & controle , Testes Genéticos/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Doença das Coronárias/tratamento farmacológico , Análise Custo-Benefício , Finlândia , Testes Genéticos/economia , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde)/economia , Avaliação de Resultados (Cuidados de Saúde)/métodos , Prevenção Primária/economia , Prevenção Primária/métodos , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco
14.
Kardiol Pol ; 77(2): 217-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30676640

RESUMO

BACKGROUND: An imbalance between the activity of matrix metalloproteinases (MMPs), particularly gelatinases, and tissue inhibitors of metalloproteinases (TIMPs) is considered as one of the mechanisms leading to aortocoronary graft failure. AIM: We aimed to assess the variability in gelatinase expression in the walls of aortocoronary conduits and to evaluate its impact on coronary artery bypass grafting (CABG) outcomes. METHODS: The study included 101 consecutive patients (61 men and 40 women) who underwent CABG. An immunohisto-chemical analysis of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression was performed on the cross-sections of the internal thoracic artery (ITA), radial artery (RA), and saphenous vein (SV). The histological findings were compared between patients with SV graft disease (SVGD[+] group) and those without occlusions in the SV (SVGD[-] group). RESULTS: The median MMP and TIMP expression was the weakest in the ITA wall. MMP expression was comparable between the RA and SV cross-sections, whereas TIMP expression was stronger in the RA than in the SV wall (p < 0.05). In most SV segments, but not in the arteries, immunostaining intensity for MMP was comparable to or stronger than for TIMPs. In the veins harvested from the SVGD(+) group, MMP-2 and MMP-9 tissue expression was more pronounced than in the SVGD(-) group. TIMP levels were comparable between groups. CONCLUSIONS: Imbalance in the metalloproteinase-to-inhibitor tissue expression in the vessel wall might predispose to graft failure. A stronger expression of TIMPs than MMPs in the arterial grafts might explain favourable long-term outcomes.


Assuntos
Vasos Sanguíneos/enzimologia , Ponte de Artéria Coronária , Doença das Coronárias/enzimologia , Gelatinases/genética , Inibidores Teciduais de Metaloproteinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasos Sanguíneos/metabolismo , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Doença das Coronárias/cirurgia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Radial/enzimologia , Artéria Radial/metabolismo , Veia Safena/enzimologia , Veia Safena/metabolismo , Artérias Torácicas/enzimologia , Artérias Torácicas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Resultado do Tratamento
15.
PLoS One ; 14(1): e0210909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30673762

RESUMO

Circulating biomarkers available in clinical practice do not allow to stratify patients with coronary heart disease (CHD) prior the onset of a clinically relevant event. We evaluated the methylation status of specific genomic segments and gene expression in peripheral blood of patients undergoing Cardiac Computed Tomography (CCT) for CHD (n = 95). We choose to investigate cholesterol metabolism. Methylation and gene expression of low density lipoprotein receptor (LDLR), sterol regulatory element-binding factor 2 (SREBF2) and ATP-binding cassette transporter 1 (ABCA1) were evaluated by qRT-PCR. Calcium score (CACS), stenosis degree, total plaque volume (TPV), calcified plaque volume (CPV), non-calcified plaque volume (NCPV) and plaque burden (PB) were assessed in all CHD patients (n = 65). The percentage of methylation at the specific analyzed segment of LDLR promoter was higher in CHD patients vs healthy subjects (HS) (n = 30) (p = 0.001). LDLR, SREBF2 and ABCA1 mRNAs were up-regulated in CHD patients vs HS (p = 0.02; p = 0.019; p = 0.008). SREBF2 was overexpressed in patients with coronary stenosis ≥50% vs subjects with stenosis <50% (p = 0.036). After adjustment for risk factors and clinical features, ABCA1 (p = 0.005) and SREBF2 (p = 0.010) gene expression were identified as independent predictors of CHD and severity. ROC curve analysis revealed a good performance of ABCA1 on predicting CHD (AUC = 0.768; p<0.001) and of SREBF2 for the prediction of disease severity (AUC = 0.815; p<0.001). Moreover, adjusted multivariate analysis demonstrated SREBF2 as independent predictor of CPV, NCPV and TPV (p = 0.022; p = 0.002 and p = 0.006) and ABCA1 as independent predictor of NCPV and TPV (p = 0.002 and p = 0.013). CHD presence and characteristics are related to selected circulating transcriptional and epigenetic-sensitive biomarkers linked to cholesterol pathway. More extensive analysis of CHD phenotypes and circulating biomarkers might improve and personalize cardiovascular risk stratification in the clinical settings.


Assuntos
Doença das Coronárias/sangue , Doença das Coronárias/genética , Epigênese Genética , Transportador 1 de Cassete de Ligação de ATP/genética , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Angiografia por Tomografia Computadorizada , Doença das Coronárias/diagnóstico por imagem , Metilação de DNA , Feminino , Expressão Gênica , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/genética , Regiões Promotoras Genéticas , Receptores de LDL/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
16.
Medicine (Baltimore) ; 98(4): e14130, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30681575

RESUMO

INTRODUCTION: As a member of B-cell lymphoma-2 (BCL-2) gene family, BCL-2 associated X (BAX) is important for cell apoptosis. In this work, we investigated the association of BAX promoter DNA methylation with coronary heart disease (CHD) in Han Chinese. METHODS: A SYBR green-based quantitative methylation specific PCR (qMSP) was used to test BAX methylation levels in 959 CHD cases and 514 controls. RESULTS: Although BAX methylation was not associated with CHD in the total samples, further breakdown analysis by age showed that BAX hypermethylation was significantly associated with CHD for individuals aged over 70 (median percentage of methylation ratio [PMR], 10.70% in cases versus (vs) 2.25% in controls, P =.046). Moreover, BAX methylation was associated with smoking and lipoprotein A (Lp(a)) for individuals aged over 70 (CHD: smoking P = .012, Lp(a) P = .001; non-CHD: smoking P = .051, Lp(a) P = .004). Further analysis of Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data showed BAX expression was upregulated by 5-aza-2'-deoxycytidine demethylation agent (fold = 1.66, P = .038) and inversely correlated with BAX methylation (r = -0.428, P = 8E-05). CONCLUSIONS: Our study supported that BAX hypermethylation might contribute to CHD risk via downregulation of BAX expression for individuals aged over 70.


Assuntos
Fatores Etários , Doença das Coronárias/genética , Metilação de DNA/genética , Proteína X Associada a bcl-2/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Decitabina/metabolismo , Feminino , Humanos , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/genética , Regulação para Cima
17.
Mol Genet Genomic Med ; 7(3): e550, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30623606

RESUMO

BACKGROUND: Regulator of telomere elongation helicase 1 (RTEL1), a telomere length-related gene, is closely linked to cancer and age-related diseases. The aim of this study was to investigate the association between genetic polymorphisms in the RTEL1 gene and coronary heart disease (CHD) risk. METHODS: In this case-control study, which includes samples from 596 CHD patients and 603 healthy controls, five SNPs in RTEL1 were selected. The genotypes were studied using the Agena MassARRAY platform, and the statistical analyses were performed using the chi-square and Fisher's exact tests, genetic model analysis, and haplotype analysis. RESULTS: In the allele model, using the chi-square test, we found that the patients with the "G" allele of rs6010620 and the "C" allele of rs4809324 in the RTEL1 gene showed a decreased risk of CHD once the results were adjusted for age and gender. In the genetic model, logistic regression analyses revealed that the rs6010620 polymorphism conferred a decreased risk of CHD in the codominant model (OR = 0.52, 95% CI: 0.31-0.88, p = 0.007 for the "G/G" genotype) and the recessive model (OR = 0.49, 95% CI: 0.30-0.80, p = 0.004 for the "G/G" genotype). In addition, the haplotype "Grs6010620 Trs6010621 Trs4809324 " of RTEL1 was associated with a 0.03-fold decreased risk of CHD once the results were adjusted for age and gender (OR = 0.03, 95% CI: 0.01-0.12, p < 0.001). CONCLUSION: Our findings have demonstrated that the genetic variants of RTEL1 may have a protective role against CHD risk.


Assuntos
Doença das Coronárias/genética , DNA Helicases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
JAMA ; 321(4): 364-373, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30694319

RESUMO

Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.


Assuntos
Apolipoproteínas B/sangue , LDL-Colesterol/sangue , Doença das Coronárias/genética , Predisposição Genética para Doença , Variação Genética , Lipase Lipoproteica/genética , Receptores de LDL/genética , Triglicerídeos/sangue , Estudos de Casos e Controles , Doença das Coronárias/sangue , Feminino , Humanos , Lipase Lipoproteica/metabolismo , Mutação com Perda de Função , Masculino , Análise da Randomização Mendeliana , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
19.
Lipids Health Dis ; 18(1): 22, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670045

RESUMO

PURPOSE: This study was designed to explore the value of monitoring miR-92a in T2DM patients with coronary heart disease (CHD). MATERIALS AND METHODS: 40 ACS patients with prior history of CHD and diabetes while the onset time of diabetes preceded that of CHD by more than 2 years were enrolled as the DACS group(diabetic ACS group). 40 ACS subjects who had had a definite diagnosis of CHD for more than 2 years with no history of T2DM were recuited as the CACS group(chronic CHD with ACS group). All enrolled subjects from DACS and CACS group came from an emergency basis and diagnosed with ACS by coronary angiography. Another 68 age- and sex-matched volunteers with chronic stable CHD without diabetes history were assigned as the control group (CHD group). We examined the serum levels of miR-92a and analyzed their correlations with blood pressure, glucose level, and lipid level. RESULTS: The levels of miR-92a were significantly elevated in the DACS group compared with those of the CACS and CHD groups. Multivariate analysis showed that miR-92a, systolic blood pressure (SBP), and glycosylated hemoglobin (HbA1c) were significantly related to ACS events in patients with T2DM. Forward stepwise binary logistic regression analysis identified miR-92a as an independent predictive factor for ACS events in the patients with T2DM. CONCLUSION: An elevated circulating miR-92a level was associated with an increased risk of ACS in CHD patients with T2DM. Thus the level of miR-92a, especially combined with elevated SBP and HbA1c, may be helpful in the detection of ACS in patients with T2DM.


Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/genética , MicroRNA Circulante/sangue , Doença das Coronárias/sangue , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/complicações , MicroRNAs/sangue , Síndrome Coronariana Aguda/complicações , Adulto , Doença das Coronárias/complicações , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Análise de Regressão
20.
Phytomedicine ; 54: 159-168, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668365

RESUMO

BACKGROUND: Xueshuan-Xinmai-Ning Tablet (XXNT), a commercially available patent drug, has been extensively used in the treatment of coronary heart disease (CHD) with a satisfying therapeutic efficacy. The aim of this study was to explore the underlying pharmacological mechanisms of XXNT acting on CHD. STUDY DESIGN: An integrative pharmacology-based investigation was performed. METHOD: Putative targets of composite compounds contained in XXNT were predicted using the Drug Target Prediction Tool in the Computation Platform for Integrative Pharmacology of Traditional Chinese Medicine (TCMIP, www.tcmip.cn) and MedChem Studio. Then, an interaction network of XXNT putative targets-known CHD-related genes was constructed, and candidate XXNT targets related to its therapeutic effects on CHD were identified by calculating three major network topological features. Functional enrichment analysis was performed to investigate the specific functions and pathways involved by the candidate XXNT targets acting on CHD, which were further validated by in vitro experiments. RESULTS: A total of 742 putative targets hit 126 chemical components contained in XXNT were predicted. Following the construction of XXNT putative target-known CHD-related gene network, and the network topological feature calculation, we identified 51 candidate XXNT targets related to its therapeutic effects on CHD. Functionally, these candidate XXNT targets were significantly associated with various cardiovascular system-related pathways, sedation-related pathways, inflammatory and immune-related pathways and endocrine/metabolic system-related pathways. More importantly, the in vitro experiment validation confirmed the regulatory effects of XXNT in SRC, VEGF and VEGFR-1, which play roles in VEGF signaling pathway, based on the endothelial injury cell model. CONCLUSION: Our findings reveal that XXNT may attenuate the major pathological changes of CHD through regulating its candidate targets, which might be involved into the signal transductions in nervous-endocrine-immune-cardiovascular-metabolic system.


Assuntos
Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Redes Reguladoras de Genes/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/farmacologia , Medicina Tradicional Chinesa , Transdução de Sinais/efeitos dos fármacos , Comprimidos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA