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1.
Wiad Lek ; 73(8): 1637-1640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33055325

RESUMO

OBJECTIVE: The aim: To examine the association between polymorphisms of the IL-6 gene promoter and HF in patients with CAD and obesity. PATIENTS AND METHODS: Material and methods: 222 patients with coronary artery disease and obesity were identified. Comparison group consisted of 115 patients with coronary artery disease with normal body weight. The groups were comparable in age and sex. The exclusion group consisted of patients with severe concomitant diseases of the respiratory and digestive organs, kidneys and people with cancer. One single nucleotide polymorphisms in the interleukin-6 promoter region was analyzed. Odds ratio (OR) and 95 % confident interval (95 % CI) were calculated. RESULTS: Results: The combined course of coronary artery disease and obesity was characterized by the detection of allele C in 62 patients (27.93 %), allele G - in 160 patients (72.07 %), and genotypes CC, CG and GG - at 24 (10.81 %), 67 (30.18 %) and 131 (59.01 %) patients respectively. The results showed that the -174G allele and GG genotype in patients with coronary artery disease and obesity were associated with heart failure (OR = 2.55, 95% CI = [1.72-3.79], χ2 = 22.8; p<0.05) and (OR = 11.95, 95% CI = [3.41-41.91], χ2 = 22.5; p<0.05), whereas allele C-174 was associated with a decrease in the risk of heart failure (OR = 0.39, 95% CI = [0.26-0.58 ], χ2 = 22.75, p<0.05). CONCLUSION: Conclusions: The obtained results testify that the -174G>C polymorphism in the interleukin-6 gene is significantly associated with increased risk of heart failure in patients with coronary artery disease and obesity.


Assuntos
Doença da Artéria Coronariana , Insuficiência Cardíaca , Interleucina-6 , Obesidade , Alelos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Feminino , Insuficiência Cardíaca/genética , Humanos , Interleucina-6/genética , Masculino , Obesidade/complicações , Obesidade/genética
2.
Nat Commun ; 11(1): 4432, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887874

RESUMO

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases = 270/Ncontrols = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication = 2.19 × 10-12, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10-17, HR = 0.91 [95% CI :0.89-0.93], for MI) and Million Veteran Program (P = 9.33 × 10-36, OR = 0.95 [95% CI: 0.94-0.96], for CAD; P = 3.35 × 10-6, OR = 0.96 [95% CI: 0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.


Assuntos
Anomalias dos Vasos Coronários/genética , Genes Neoplásicos , Infarto do Miocárdio/genética , Doenças Vasculares/congênito , Proteínas ADAMTS/genética , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/genética , Cromossomos/genética , Estudos de Coortes , Doença da Artéria Coronariana/genética , Feminino , Displasia Fibromuscular/complicações , Displasia Fibromuscular/genética , Estudo de Associação Genômica Ampla , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Metanálise como Assunto , Proteínas dos Microfilamentos/genética , Fatores de Risco , Doenças Vasculares/genética
3.
Nat Commun ; 11(1): 3635, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820175

RESUMO

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.


Assuntos
Predisposição Genética para Doença , Herança Multifatorial/genética , Penetrância , Idoso , Neoplasias da Mama/genética , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Doença da Artéria Coronariana/genética , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
4.
Arterioscler Thromb Vasc Biol ; 40(9): 2095-2107, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757647

RESUMO

OBJECTIVE: Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of ß-VLDLs-the major atherogenic lipoproteins. ß-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than ß-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. CONCLUSIONS: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.


Assuntos
Doenças da Aorta/prevenção & controle , Apolipoproteína C-III/deficiência , Aterosclerose/prevenção & controle , Doença da Artéria Coronariana/prevenção & controle , Triglicerídeos/sangue , Animais , Animais Geneticamente Modificados , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteína C-III/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Lipoproteínas IDL/sangue , Fígado/metabolismo , Masculino , Oxirredução , Placa Aterosclerótica , Coelhos
5.
JAMA ; 324(8): 761-771, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32840598

RESUMO

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI. Design, Setting, and Participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and Measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16). Conclusions and Relevance: Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial Registration: ClinicalTrials.gov Identifier: NCT01742117.


Assuntos
Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/genética , Inibidores do Citocromo P-450 CYP2C19/uso terapêutico , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea/efeitos adversos , Medicina de Precisão , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticagrelor/uso terapêutico , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/cirurgia , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Clopidogrel/efeitos adversos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/terapia , Inibidores do Citocromo P-450 CYP2C19/efeitos adversos , Feminino , Genótipo , Técnicas de Genotipagem , Hemorragia/induzido quimicamente , Heterozigoto , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Testes Imediatos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Ticagrelor/efeitos adversos
6.
Medicine (Baltimore) ; 99(29): e20582, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702814

RESUMO

The morbidity of coronary artery disease (CAD) in the Uygur population of Xinjiang was much higher than the national average. Clopidogrel is the most commonly used medication worldwide in dual antiplatelet therapy for CAD, and the response of clopidogrel is affected by CYP2C19, PON1, and ABCB1 genetic polymorphisms. The distribution of CYP2C19*17, ABCB1, and PON1 genetic polymorphisms in Han and Uygur populations with CAD of Xinjiang has not been investigated.This study aimed to investigate the frequencies of CYP2C19, PON1, and ABCB1 genetic polymorphisms, and to identify the metabolizer phenotype of CYP2C19 in Han and Uygur populations with CAD in Northwestern Xinjiang, China. We identified 602 Han and 527 Uygur patients from 2014 through 2019 and studied genotypes for selected allele polymorphisms using sequencing by hybridization.There were significantly different allele frequencies and genotype frequencies between the 2 ethnic groups in terms of CYP2C19*2, *3, *17, ABCB1 and PON1, (P < .05). For CYP2C19*17, the frequency of TT genotype was 2.5% in Uygur patients, but it was undetectable in Han patients. In both the intermediate and poor metabolizer groups, the genotypes polymorphisms CYP2C19*2, *3, *17 were significantly less common in Uygur patients than in Han patients (P < .001). By contrast, the proportion of ultra-metabolizers as defined by CYP2C19*2, *3, *17 polymorphisms significantly higher in Uygur patients (18.6%) than in Han patients (1.7%, P < .001). The CYP2C19*2 frequency was significantly different between Han patients and Han healthy groups (P < .001), while the CYP2C19*3 frequency was significantly different between Uygur patients and Uygur healthy groups (P < .001).Our study supports the notion of interethnic differences in terms of CYP2C19, PON1, and ABCB1 polymorphisms and CYP2C19 genotype-defined clopidogrel metabolic groups. These finding could provide valuable data and insights into personalized CAD treatment for the Uygur and Han populations in Xinjiang.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Arildialquilfosfatase/genética , China/etnologia , Clopidogrel/uso terapêutico , Comorbidade , Doença da Artéria Coronariana/mortalidade , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Grupos Étnicos/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico
7.
Medicine (Baltimore) ; 99(27): e20924, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629690

RESUMO

Disabled-2 (Dab2) is a clathrin and cargo-binding endocytic adaptor protein that plays a role in cellular trafficking of low-density lipoprotein receptor (LDLR). However, little is known about its involvement in coronary artery disease (CAD). Here, we aimed to investigate the association between Dab2 single-nucleotide polymorphisms (SNPs) and CAD in Chinese Han and Uyghur populations.We performed a case-control study in CAD group that consisted of 621 Han and 346 Uygurs, and the age and gender matched control group consisted of 611 Han and 405 Uygurs. The clinicopathological characteristics of these subjects were analyzed. Genotyping of 4 SNPs (rs1050903, rs2855512, rs11959928, and rs2255280) of the Dab2 gene was performed in all subjects with an improved multiplex ligase detection reaction method.The distribution of the genotype, dominant model (AA vs. AC + CC), as well as allele frequencies of both rs2855512 and rs2255280, was significantly different between CAD patients and control subjects in Han population but not in Uyghur population. AA genotype may be a risk factor for CAD. For Han population, statistical significant correlation between dominant model for both SNPs (AA) and CAD was found after multivariate adjustment. After multivariate adjustment in the Han population, we speculate that rs285512 A allele and rs2255280 A allele may be potentially associated with the onset of coronary heart disease. Individuals with the AA genotype had an OR of 1.44 (95% CI: 1.10-1.88, P = .01, rs2855512) and 1.41 (95% CI: 1.08-1.85, P = .01, rs2255280) for CAD compared with individuals with the AC or CC genotype, respectively.Our data indicates that the AA genotype of rs2855512 and rs2255280 in the Dab2 gene may be a genetic marker of CAD risk in Chinese Han population.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Life Sci ; 256: 117898, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522566

RESUMO

BACKGROUND: Atherosclerosis as a progressive inflammatory disease is the main cause of Coronary Artery Disease (CAD). Multiple genetic and environmental factors are involved in susceptibility to atherosclerotic vascular diseases. FOXO1 gene acts as a key molecular proinflammatory transcription factor and the FBOX32 gene as an F-box protein plays pivotal roles in regulation of muscle atrophy and inhibition of the pathologic cardiac hypertrophy. MiR-27a has been reported to contribute to atherosclerosis prevention and the inflammatory processes of atherosclerosis. MicroRNA-23a has been found to promote atherosclerotic plaque progression and vulnerability. Hence, given the importance of these subjects, the present study was carried out to investigate the expression levels of the desired genes. METHODOLOGY: In this case-control study, 82 patients with CAD and 80 healthy controls were investigated. Expression levels of miRNAs -27a and 23a, FOXO1, Sirtuin 1 (SIRT1) in the Peripheral Blood Mononuclear Cells (PBMCs), serum concentration of IL6 and TNF-α of the studied subjects were evaluated using the real-time Polymerase Chain Reaction (PCR) technique. The correlation between the variables was also investigated. RESULTS: Results of the study demonstrated that expression of FOXO1, IL-6, TNF-α, miR-27a, and miR-23a increased in the PBMCs of the patients with CAD and their expression levels were significantly correlated with the severity of stenosis. A significant decrease was observed in the expression of SIRT1 in the patients with CAD compared to the healthy controls. Furthermore, the Receiver Operating Characteristic (ROC) curve was plotted to find the effectiveness of FOXO1 and miRNA-27a gene expression as a diagnostic marker for CAD. CONCLUSIONS: Findings of the study suggested that miRs-27a and FOXO1 genes have a potential role in the progression of atherosclerosis and mediate the molecular and genetic disturbances of the intracellular communication in the atherosclerosis.


Assuntos
Doença da Artéria Coronariana/sangue , Citocinas/sangue , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica , Mediadores da Inflamação/sangue , Leucócitos Mononucleares/metabolismo , MicroRNAs/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Feminino , Proteína Forkhead Box O1/genética , Humanos , Modelos Lineares , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Sirtuína 1/genética , Sirtuína 1/metabolismo
10.
Medicine (Baltimore) ; 99(22): e20494, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481463

RESUMO

Aims to explore the interaction between serum selenium level and CYP4F2 and CTRP9 gene polymorphisms in the development of coronary artery disease (CAD).A total of 200 cases of CAD were selected from the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei, China, and 200 healthy subjects cases were served as controls. The polymorphism of CYP4F2 and CTRP9 gene was detected by Sanger sequencing, and the serum selenium level was measured by hydride generation atomic fluorescence spectrometry.The serum selenium level in the CAD group was significantly lower than that in the control group. The risk of CAD was decreased in the patients carrying the AA genotype in CYP4F2 rs3093135, while the frequency of the CC genotype of CTRP9 rs9553238 in CAD patients was higher than that in control subjects. Low serum selenium level and CTRP9 rs9553238 CC genotype play a positive role in the occurrence of CAD.The serum selenium level is negatively correlated with CAD. The polymorphism of the CYP4F2 rs3093135 and CTRP9 rs9553238 was significantly related to the susceptibility of CAD, and there is a synergistic effect between the serum selenium level and the CTRP9 rs9553238 CC genotype, which significantly increases the risk of CAD.


Assuntos
Adiponectina/genética , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Família 4 do Citocromo P450/genética , Selênio/sangue , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
BMJ ; 369: m1203, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376654

RESUMO

OBJECTIVE: To evaluate whether body size in early life has an independent effect on risk of disease in later life or whether its influence is mediated by body size in adulthood. DESIGN: Two sample univariable and multivariable mendelian randomisation. SETTING: The UK Biobank prospective cohort study and four large scale genome-wide association studies (GWAS) consortiums. PARTICIPANTS: 453 169 participants enrolled in UK Biobank and a combined total of more than 700 000 people from different GWAS consortiums. EXPOSURES: Measured body mass index during adulthood (mean age 56.5) and self-reported perceived body size at age 10. MAIN OUTCOME MEASURES: Coronary artery disease, type 2 diabetes, breast cancer, and prostate cancer. RESULTS: Having a larger genetically predicted body size in early life was associated with an increased odds of coronary artery disease (odds ratio 1.49 for each change in body size category unless stated otherwise, 95% confidence interval 1.33 to 1.68) and type 2 diabetes (2.32, 1.76 to 3.05) based on univariable mendelian randomisation analyses. However, little evidence was found of a direct effect (ie, not through adult body size) based on multivariable mendelian randomisation estimates (coronary artery disease: 1.02, 0.86 to 1.22; type 2 diabetes:1.16, 0.74 to 1.82). In the multivariable mendelian randomisation analysis of breast cancer risk, strong evidence was found of a protective direct effect for larger body size in early life (0.59, 0.50 to 0.71), with less evidence of a direct effect of adult body size on this outcome (1.08, 0.93 to 1.27). Including age at menarche as an additional exposure provided weak evidence of a total causal effect (univariable mendelian randomisation odds ratio 0.98, 95% confidence interval 0.91 to 1.06) but strong evidence of a direct causal effect, independent of early life and adult body size (multivariable mendelian randomisation odds ratio 0.90, 0.85 to 0.95). No strong evidence was found of a causal effect of either early or later life measures on prostate cancer (early life body size odds ratio 1.06, 95% confidence interval 0.81 to 1.40; adult body size 0.87, 0.70 to 1.08). CONCLUSIONS: The findings suggest that the positive association between body size in childhood and risk of coronary artery disease and type 2 diabetes in adulthood can be attributed to individuals remaining large into later life. However, having a smaller body size during childhood might increase the risk of breast cancer regardless of body size in adulthood, with timing of puberty also putatively playing a role.


Assuntos
Adiposidade/genética , Neoplasias da Mama/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Obesidade/genética , Neoplasias da Próstata/epidemiologia , Índice de Massa Corporal , Neoplasias da Mama/genética , Criança , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/genética , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia
13.
PLoS One ; 15(5): e0232735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379805

RESUMO

BACKGROUND: Atherosclerosis is the primary cause of coronary artery disease (CAD). Several observational studies have examined the association of traditional CAD risk factors with the progression of coronary artery calcification (CAC). In our study we investigated the effect of 11 different genetic risk scores associated with CAD and CAD risk factors on the progression of CAC. METHODS AND RESULTS: We included 3097 participants from the Heinz Nixdorf Recall study who had available CAC measurements at baseline (CACb) and at the 5-year follow-up (CAC5y). A weighted genetic risk score for CAD and each of the CAD-associated risk factors was constructed. Multiple regression analyses were applied to i) the difference between the observed log(CAC5y+1) (log(obs)) and expected log(CAC5y+1) (log(exp)) at the 5-year follow-up following the individual's log(CACb+1) percentile for the time between scans (log(obs)-log(exp)) and ii) the 5-year CAC progression, defined as 5*(log(CAC5y+1)-log(CACb+1))/time between the scans, adjusted for age, sex, and log(CACb+1) as well as for risk factors. The median percent deviation from the expected (CAC5y+1) and the 5-year progression of (CAC+1) in our study were 0 (first quartile: Q1; third quartile: Q3: -0.32; 0.48) and 45.4% (0%; 171.0%) respectively. In the age-, sex- and log(CACb+1)-adjusted model, the per-standard deviation (SD) increase in CAD genetic risk score was associated with the percent deviation from the expected (CAC5y+1) (9.7% (95% confidence interval: 5.2%; 14.5%), p = 1.6x10-5) and the 5-year progression of CAC (7.1% (3.0%; 11.4%), p = 0.0005). The CAD genetic risk score explains an additional 0.6% of the observed phenotypic variance for "log(obs)-log(exp)" and 0.4% for 5-year progression of CAC. Additionally, the per-SD increase in the CAC genetic risk score was associated with the percent deviation from the expected (CAC5y+1) (6.2% (1.9%; 10.8%, p = 0.005)) explaining an additional 0.2% of the observed phenotypic variance. However, the per-SD increase in the CAC genetic risk score was not associated with the 5-year progression of CAC (4.4% (0.4%; 8.5%), p = 0.03) after multiple testing. Adjusting for risk factors did not change the results. None of the other genetic risk scores showed an association with the percent deviation from the expected (CAC5y+1) or with the 5-year progression of CAC. CONCLUSIONS: The association of the CAC genetic risk score and the CAD genetic risk score provides evidence that genetic determinants for CAC and CAD influence the progression of CAC.


Assuntos
Doença da Artéria Coronariana/genética , Vasos Coronários/patologia , Calcificação Vascular/genética , Idoso , Doença da Artéria Coronariana/patologia , Vasos Coronários/metabolismo , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Calcificação Vascular/patologia
14.
Life Sci ; 255: 117837, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450175

RESUMO

Atherosclerosis is a common cause of cardiovascular and cerebrovascular diseases. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) have attracted substantial attention for their roles in various physiological and pathological processes. In recent years, research on the roles of circRNAs in atherosclerosis has progressed rapidly, and they have been implicated in the pathophysiological processes underlying the development of atherosclerosis, including changes in the functions of endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages. In this review article, we summarize currently available data regarding the role of circRNAs in atherosclerosis and how circRNAs influence the development of atherosclerosis by regulating ECs, VSMCs, and macrophages. We also discuss their potential as diagnostic biomarkers for coronary artery disease.


Assuntos
Aterosclerose/fisiopatologia , RNA Circular/genética , Animais , Aterosclerose/genética , Biomarcadores/análise , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Células Endoteliais/patologia , Humanos , Macrófagos/patologia , Miócitos de Músculo Liso/patologia
15.
DNA Cell Biol ; 39(7): 1347-1355, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32352837

RESUMO

The aim of this study was to evaluate the association of the IL-12B polymorphisms with the presence of premature coronary artery disease (pCAD) and with cardiovascular risk factors. The study included 2163 individuals (1133 patients with pCAD and 1030 healthy controls). Seven IL-12B polymorphisms (rs1363670, rs3212220, rs3212227, rs6887695, rs1433048, rs2853694, and rs1368439) were determined by TaqMan assays. The associations were evaluated by logistic regression using inheritance models adjusted for confounding variables. The rs1363670 was associated with a low risk of pCAD (odds ratio [OR] 0.718, pdominant = 0.034; OR 0.701, pheterozygote = 0.024; OR 0.702, pcodominant1 = 0.025). The association of the polymorphisms with cardiovascular risk factors was evaluated independently in each group. In controls, the rs3212227, rs3212220, and rs6887695 polymorphisms were associated with subcutaneous abdominal fat > p75, whereas the rs6887695 was associated with a high risk of central obesity. In pCAD patients, the rs2853694 was associated with a low risk of insulin resistance; and association of rs3212227 and rs3212220 with a low risk of metabolic syndrome was found, and the rs6887695 polymorphism was nominally associated with a high risk of hyperuricemia. In conclusion, the IL-12B rs1363670 polymorphism was associated with a low risk of pCAD, and in both pCAD patients and healthy controls, some IL-12B polymorphisms were associated with cardiovascular risk factors.


Assuntos
Aterosclerose/genética , Doença da Artéria Coronariana/genética , Subunidade p40 da Interleucina-12/genética , Polimorfismo de Nucleotídeo Único , Doença da Artéria Coronariana/epidemiologia , Feminino , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco
16.
Gene ; 750: 144722, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32360841

RESUMO

BACKGROUND: The United Arab Emirates (UAE) population has a high rate of type 2 diabetes mellitus (T2DM) and other metabolic risk factors for coronary artery disease (CAD). Previous studies have indicated strong genetic associations between T2DM and CAD. The objective of this study was to replicate previously reported significant genetic associations for T2DM and CAD which were in a genome-wide significance level in a cohort from the Arab population of the UAE, and to investigate the associations of these loci with twelve cardiometabolic traits that may influence the development of T2DM and CAD. METHODS: A total of nine hundreds and fourteen Emiratis were recruited to this study to investigate associations of 101 loci for T2DM (422 patients and 455 controls), and 53 loci for CAD (160 patients and 245 controls), using logistic regression models which incorporating possible confounding factors. Results are presented using odds ratios with their corresponding 95% confidence intervals and p-values. Linear regression models, which included possible covariates were applied to determine any associations between the T2DM and CAD reported loci with the twelve cardiometabolic traits and results were presented as effect sizes (beta), standard errors, and p-values. Furthermore, the overall risks for all the loci found to be associated with T2DM and CAD were determined using the cumulative effects of the risk alleles. For those found to be associated with the twelve cardiometabolic traits, risks were determined using calculations of their polygenic risk scores. RESULTS: The mean age of the T2DM group was 61.5 ± 11.3 and of the CAD group was 66.2 ± 9.3 years. The prevalence of most of the cardiovascular disease risk factors in this cohort were high: mean body mass index (BMI) = 29.4, T2DM (51.9%), hypertension (60.9%), dyslipidemia (68.8%), and smoking (47.9%). All individuals who were tested for CAD (n = 405) also had a diagnosis of T2DM. The highest association variant for T2DM was in SNP rs1977833 in HHEX (p = 0.0016, OR = 0.56 for allele A), which is a multi-ethnic locus for T2DM. The strongest association with CAD was detected with SNP rs264 in LPL, which encodes lipoprotein lipase (p = 0.009, OR = 1.96 for allele A). For the cardiometabolic traits analyses, most notable associations were those of FTO with BMI and waist circumference; ABO with height; KCNK16 with diastolic blood pressure; PROX1-AS1, GCKR, and MIR129-LEP with fasting blood glucose; random blood glucose with ZEB2 and THADA; HbA1c levels with TLE1 and FAM99B loci; HDL-cholesterol levels with BRAF; and triglyceride levels with ZEB2. Furthermore, accumulation of risk alleles and polygenic scores of the associated loci was clearly associated with increased risks for all tested diseases and traits in this cohort. CONCLUSIONS: The present study highlighted many known genetic loci, which are linked to T2DM and CAD and their associations with major cardiometabolic traits in Arab descendants. We confirmed that some loci are associated with T2DM, CAD, and metabolic traits independently of the ethnic background, with a novel association also detected between height and ABO.


Assuntos
Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Miocárdio/metabolismo , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Razão de Chances , Fatores de Risco , Emirados Árabes Unidos/epidemiologia , Circunferência da Cintura
17.
Nutr Metab Cardiovasc Dis ; 30(6): 960-966, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32402592

RESUMO

BACKGROUND AND AIMS: Mitochondrial DNA (mtDNA) haplogroups have been associated with the development of coronary artery disease (CAD) in European populations. However, the specific mtDNA haplogroups associated with CAD have not been investigated in Chinese populations. METHODS AND RESULTS: Here, we carried out a case-control study including 1036 and 481 CAD patients and 973 and 511 geographically matched asymptomatic control subjects in southern and northern China, respectively. After adjusting for age and gender, our results indicated that mtDNA haplogroups are not associated with the occurrence of CAD and its subcategories, acute coronary syndromes and stable coronary heart disease, in both southern and northern Chinese populations. By focusing on the southern Chinese population, we further revealed that mtDNA haplogroups are not associated with CAD severity. Type 2 diabetes (T2D) and hypertension are two key driving factors for the development of CAD, nonetheless, we found that the frequencies of the 12 studied mtDNA haplogroups did not differ between patients with and without T2D or hypertension. CONCLUSION: mtDNA haplogroups are not associated with the occurrence of CAD or its subcategories in Chinese populations. Other factors such as environment and nuclear genetic background may contribute to the occurrence of CAD.


Assuntos
Síndrome Coronariana Aguda/genética , Doença da Artéria Coronariana/genética , DNA Mitocondrial/genética , Variação Genética , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
18.
Gene ; 753: 144805, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32445923

RESUMO

Genomic variants in both ADTRP and TFPI genes are associated with risk of coronary artery disease (CAD). ADTRP regulates TFPI expression and endothelial cell functions involved in the initiation of atherosclerotic CAD. ADTRP also specifies primitive myelopoiesis and definitive hematopoiesis by upregulating TFPI expression. However, the underlying molecular mechanism is unknown. Here we show that transcription factor POU1F1 is the key by which ADTRP regulates TFPI expression. Luciferase reporter assays, chromatin-immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) in combination with analysis of large and small deletions of the TFPI promoter/regulatory region were used to identify the molecular mechanism by which ADTRP regulates TFPI expression. Genetic association was assessed using case-control association analysis and phenome-wide association analysis (PhenGWA). ADTRP regulates TFPI expression at the transcription level in a dose-dependent manner. The ADTRP-response element was localized to a 50 bp region between -806 bp and -756 bp upstream of TFPI transcription start site, which contains a binding site for POU1F1. Deletion of POU1F1-binding site or knockdown of POU1F1 expression abolished ADTRP-mediated transcription of TFPI. ChIP and EMSA demonstrated that POU1F1 binds to the ADTRP response element. Genetic analysis identified significant association between POU1F1 variants and risk of CAD. PhenGWA identified other phenotypic traits associated with the ADTRP-POU1F1-TFPI axis such as lymphocyte count (ADTRP), waist circumference (TFPI), and standing height (POU1F1). These data identify POU1F1 as a transcription factor that regulates TFPI transcription in response to ADTRP, and link POU1F1 variants to risk of CAD for the first time.


Assuntos
Doença da Artéria Coronariana/metabolismo , Lipoproteínas/biossíntese , Proteínas de Membrana/metabolismo , Fator de Transcrição Pit-1/metabolismo , Aterosclerose/genética , Estudos de Casos e Controles , Linhagem Celular , Imunoprecipitação da Cromatina/métodos , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas , Células Endoteliais/metabolismo , Genes Homeobox , Células HeLa , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Regiões Promotoras Genéticas , Elementos de Resposta , Sítio de Iniciação de Transcrição , Transcrição Genética
19.
Gene ; 753: 144806, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32461018

RESUMO

BACKGROUND: The aim of the present study was to detect potential gender-specific associations between some common CD36 single nucleotide polymorphisms (SNPs) and the lipid profile, as well as the susceptibility to premature multi-vessel coronary artery heart disease (CHD) in the Han population of Northern China. METHODS: A systematic three-step study process was employed to detect associations between CD36 gene variants and blood lipid profiles, as well as premature multi-vessel CHD in a gender-specific manner. RESULTS: The current study documented the following novel findings: (I) the full population-based association study in 329 Northern Han Chinese showed that four common CD36 polymorphisms were significantly related to extreme lipid profiles, with statistically significant effects based on gender interactions (rs1049673: P = 0.001; rs7755: P = 0.008; rs3211956: P = 0.034; and rs3173798: P = 0.004); (ii) these statistically significant effects could be decomposed into statistically significant atherogenic effects in males, but non-significant non-atherogenic effects in females; (iii) the results of logistic regression analysis indicated that current smoking status, low density lipoprotein cholesterol (LDL-C) levels, and type-2 diabetes were independent risk factors for premature multi-vessel CHD phenotype (P < 0.0001). CONCLUSIONS: Four common CD36 polymorphisms (rs1049673, rs7755, rs3211956, and rs3173798) were identified to be significantly associated with extreme lipid profiles and had statistically opposite gender-specific clinical lipid profile effects. Thus, the 3'-untranslated regions (3'-UTR) CD36 SNPs could be a novel target for metabolic abnormalities in males of the Han nationality from Northern China.


Assuntos
Antígenos CD36/genética , Doença da Artéria Coronariana/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Grupos Étnicos/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Caracteres Sexuais
20.
Curr Cardiol Rev ; 16(3): 198-201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392116

RESUMO

Like other adipokines, omentin-1 is secreted from visceral adipose tissue and plays a vital role in the development of chronic inflammatory diseases, including cardiovascular events. Recent studies have shown that circulating omentin-1 levels are associated with various metabolic risk factors, such as high blood pressure, increased waist circumference, dyslipidemia, and glucose intolerance. The decrease in serum omentin level is an independent predictor of Coronary Artery Disease (CAD) and is associated with the severity of this disease. Since there is no relevant review in the literature, we aimed to summarize the studies on the relationship between omentin-1 and CAD.


Assuntos
Doença da Artéria Coronariana/genética , Citocinas/genética , Lectinas/genética , Doença da Artéria Coronariana/patologia , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Masculino , Fatores de Risco
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