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1.
Nat Commun ; 12(1): 5276, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489429

RESUMO

A promise of genomics in precision medicine is to provide individualized genetic risk predictions. Polygenic risk scores (PRS), computed by aggregating effects from many genomic variants, have been developed as a useful tool in complex disease research. However, the application of PRS as a tool for predicting an individual's disease susceptibility in a clinical setting is challenging because PRS typically provide a relative measure of risk evaluated at the level of a group of people but not at individual level. Here, we introduce a machine-learning technique, Mondrian Cross-Conformal Prediction (MCCP), to estimate the confidence bounds of PRS-to-disease-risk prediction. MCCP can report disease status conditional probability value for each individual and give a prediction at a desired error level. Moreover, with a user-defined prediction error rate, MCCP can estimate the proportion of sample (coverage) with a correct prediction.


Assuntos
Predisposição Genética para Doença/genética , Aprendizado de Máquina , Herança Multifatorial/genética , Fatores Etários , Bancos de Espécimes Biológicos , Neoplasias da Mama/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Reprodutibilidade dos Testes , Esquizofrenia/genética , Suécia , Reino Unido
2.
J Int Med Res ; 49(7): 3000605211019263, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34275374

RESUMO

OBJECTIVE: To investigate the relationship between angiotensin (AGT) rs2493132 gene polymorphism and the risk of developing non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population. METHODS: Polymerase chain reaction was performed to determine AGT genotypes. Anthropometric and clinical data were investigated and statistically analyzed in the clinical laboratory department of Qingdao Municipal Hospital. RESULTS: The AGT rs2493132 CT + TT genotype was an important risk factor for CAD in patients with NAFLD and NAFLD + CAD in healthy controls. The AGT rs2493132 T allele increased the risk of NAFLD + CAD in healthy controls. The AGT rs2493132 CT + TT genotype and T allele also significantly increased the risk of CAD in patients with NAFLD after adjustments for age, sex, and body mass index. In addition, AGT rs2493132 T allele carriers showed higher total cholesterol (TC) and low-density lipoprotein (LDL) levels compared with non-carriers. CONCLUSIONS: The AGT rs2493132 CT + TT genotype and T allele significantly increased the risk of developing CAD in patients with NAFLD in the Chinese Han population. The AGT rs2493132 T allele was associated with increased serum TC and LDL levels.


Assuntos
Doença da Artéria Coronariana , Hepatopatia Gordurosa não Alcoólica , Angiotensinogênio , Angiotensinas , Grupo com Ancestrais do Continente Asiático/genética , China , Doença da Artéria Coronariana/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
3.
Medicina (Kaunas) ; 57(6)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199767

RESUMO

Background and Objectives: Tumor necrosis factor alpha (TNF-α) is proatherogenic and associated with the risk of acute ischemic events, although the mechanisms that regulate TNF-α expression in stable coronary artery disease (SCAD) are not fully understood. We investigated whether metabolic, inflammatory, and epigenetic (microRNA (miRNA)) markers are associated with TNF-α expression in SCAD. Materials and Methods: Patients with SCAD were prospectively recruited and their metabolic and inflammatory profiles were assessed. TNF-α levels were assessed using an enzyme-linked immunosorbent assay. The relative expression of six circulating miRNAs associated with the regulation of inflammation and/or atherosclerosis was determined. Results: Of the 24 included patients with the mean age of 65 (9) years, 88% were male, and 54% were diabetic. The TNF-α levels were (median (interquartile range)) 1.0 (0.7-1.1) pg/mL. The percentage of glycosylated hemoglobin (r = 0.418, p = 0.042), serum triglyceride levels (r = 0.429, p = 0.037), and C-reactive protein levels (r = 0.407, p = 0.048) were positively correlated with TNF-α levels. Of the candidate miRNAs, miR-146a expression levels were negatively correlated with TNF-α levels (as indicated by r = 0.500, p = 0.035 for correlation between delta cycle threshold (ΔCt) miR-146a and TNF-α levels). In multivariate analysis, serum triglyceride levels and miR-146a expression levels were independently associated with TNF-α levels. miR-146 expression levels were not associated with metabolic or other inflammatory parameters and were negatively correlated with the number of coronary vessels with obstructive disease (as indicated by r = 0.556, p = 0.017 for correlation between ΔCt miR-146a and number of diseased vessels). Conclusions: miR-146a expression levels were negatively correlated with TNF-α levels in patients with SCAD, irrespective of other metabolic or inflammatory markers, and with the severity of coronary artery disease. The results add to the knowledge on the role of miR-146a in TNF-α-based inflammation in SCAD and support future research on the potential therapeutic use of miR-146a in such a clinical scenario.


Assuntos
Doença da Artéria Coronariana , MicroRNAs , Idoso , Biomarcadores , Doença da Artéria Coronariana/genética , Feminino , Humanos , Inflamação , Masculino , MicroRNAs/genética , Fator de Necrose Tumoral alfa
4.
Arterioscler Thromb Vasc Biol ; 41(9): 2494-2508, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34233476

RESUMO

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.


Assuntos
HDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Hiperlipoproteinemia Tipo II/genética , Proteínas de Transporte de Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Análise da Randomização Mendeliana , México/epidemiologia , Camundongos , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleotídeos/metabolismo , Fenótipo , Medição de Risco
5.
Genes (Basel) ; 12(6)2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205376

RESUMO

Primary prevention is crucial for coronary heart disease (CAD) and the identification of new reliable biomarkers might help risk stratification or predict adverse coronary events. Alternative splicing (AS) is a less investigated genetic factors implicated in CAD etiology. We performed an RNA-seq study on PBMCs from CAD patients and control subjects (CTR) and observed 113 differentially regulated AS events (24 up and 89 downregulated) in 86 genes. The RECK (Reversion-inducing-cysteine-rich protein with Kazal motifs) gene was further analyzed in a larger case study (24 CTR subjects, 72 CAD and 32 AMI patients) for its Splicing-Index FC (FC = -2.64; p = 0.0217), the AS event involving an exon (exon 18), and its role in vascular inflammation and remodeling. We observed a significant downregulation of Long RECK splice variant (containing exon 18) in PBMCs of AMI compared to CTR subjects (FC = -3.3; p < 0.005). Interestingly, the Short RECK splice variant (lacking exon 18) was under-expressed in AMI compared to both CTR (FC = -4.5; p < 0.0001) and CAD patients (FC = -4.2; p < 0.0001). A ROC curve, constructed combining Long and Short RECK expression data, shows an AUC = 0.81 (p < 0.001) to distinguish AMI from stable CAD patients. A significant negative correlation between Long RECK and triglycerides in CTR group and a positive correlation in the AMI group was found. The combined evaluation of Long and Short RECK expression levels is a potential genomic biomarker for the discrimination of AMI from CAD patients. Our results underline the relevance of deeper studies on the expression of these two splice variants to elucidate their functional role in CAD development and progression.


Assuntos
Processamento Alternativo , Doença da Artéria Coronariana/genética , Proteínas Ligadas por GPI/genética , Infarto do Miocárdio/genética , Idoso , Biomarcadores/metabolismo , Células Cultivadas , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Projetos Piloto
6.
Biomolecules ; 11(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209965

RESUMO

Extracellular circulating microRNAs (miRNAs) are currently a focus of interest as non-invasive biomarkers of cardiovascular pathologies, including coronary artery disease (CAD) and acute coronary syndromes (ACS): myocardial infarction with and without ST-segment elevation (STEMI and NSTEMI) and unstable angina (UA). However, the current data for some miRNAs are controversial and inconsistent, probably due to pre-analytical and methodological variances in different studies. In this work, we fulfilled the basic pre-analytical requirements provided for circulating miRNA studies for application to stable CAD and ACS research. We used quantitative PCR to determine the relative plasma levels of eight circulating miRNAs that are potentially associated with atherosclerosis. In a cohort of 136 adult clinic CAD patients and outpatient controls, we found that the plasma levels of miR-21-5p and miR-146a-5p were significantly elevated in ACS patients, and the level of miR-17-5p was decreased in ACS and stable CAD patients compared to both healthy controls and hypertensive patients without CAD. Within the ACS patient group, no differences were found in the plasma levels of these miRNAs between patients with positive and negative troponin, nor were any differences found between STEMI and NSTEMI. Our results indicate that increased plasma levels of miR-146a-5p and miR-21-5p can be considered general ACS circulating biomarkers and that lowered miR-17-5p can be considered a general biomarker of CAD.


Assuntos
MicroRNA Circulante/análise , Doença da Artéria Coronariana/genética , MicroRNAs/análise , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/genética , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Estudos de Coortes , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue
7.
Curr Cardiol Rep ; 23(8): 107, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196841

RESUMO

PURPOSE OF THE REVIEW: Coronary artery disease (CAD) is a common disease globally attributable to the interplay of complex genetic and lifestyle factors. Here, we review how genomic sequencing advances have broadened the fundamental understanding of the monogenic and polygenic contributions to CAD and how these insights can be utilized, in part by creating polygenic risk estimates, for improved disease risk stratification at the individual patient level. RECENT FINDINGS: Initial studies linking premature CAD with rare familial cases of elevated blood lipids highlighted high-risk monogenic contributions, predominantly presenting as familial hypercholesterolemia (FH). More commonly CAD genetic risk is a function of multiple, higher frequency variants each imparting lower magnitude of risk, which can be combined to form polygenic risk scores (PRS) conveying significant risk to individuals at the extremes. However, gaps remain in clinical validation of PRSs, most notably in non-European populations. With improved and more broadly utilized genomic sequencing technologies, the genetic underpinnings of coronary artery disease are being unraveled. As a result, polygenic risk estimation is poised to become a widely used and powerful tool in the clinical setting. While the use of PRSs to augment current clinical risk stratification for optimization of cardiovascular disease risk by lifestyle change or therapeutic targeting is promising, we await adequately powered, prospective studies, demonstrating the clinical utility of polygenic risk estimation in practice.


Assuntos
Doença da Artéria Coronariana , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Humanos , Herança Multifatorial/genética , Estudos Prospectivos , Fatores de Risco
8.
Transl Psychiatry ; 11(1): 368, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34226488

RESUMO

Neuroticism is associated with poor health, cardiovascular disease (CVD) risk factors and coronary artery disease (CAD). The conditional/conjunctional false discovery rate method (cond/conjFDR) was applied to genome wide association study (GWAS) summary statistics on neuroticism (n = 432,109), CAD (n = 184,305) and 12 CVD risk factors (n = 188,577-339,224) to investigate genetic overlap between neuroticism and CAD and CVD risk factors. CondFDR analyses identified 729 genomic loci associated with neuroticism after conditioning on CAD and CVD risk factors. The conjFDR analyses revealed 345 loci jointly associated with neuroticism and CAD (n = 30), body mass index (BMI) (n = 96) or another CVD risk factor (n = 1-60). Several loci were jointly associated with neuroticism and multiple CVD risk factors. Seventeen of the shared loci with CAD and 61 of the shared loci with BMI are novel for neuroticism. 21 of 30 (70%) neuroticism risk alleles were associated with higher CAD risk. Functional analyses of the genes mapped to the shared loci implicated cell division, nuclear receptor, elastic fiber formation as well as starch and sucrose metabolism pathways. Our results indicate polygenic overlap between neuroticism and CAD and CVD risk factors, suggesting that genetic factors may partly cause the comorbidity. This gives new insight into the shared molecular genetic basis of these conditions.


Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Doenças Cardiovasculares/genética , Doença da Artéria Coronariana/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores de Risco de Doenças Cardíacas , Humanos , Neuroticismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
9.
Eur J Intern Med ; 90: 49-65, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34092486

RESUMO

BACKGROUND: Antiplatelet agent clopidogrel has been widely used for stroke management for many years, although resistance to clopidogrel may increase the chance of stroke recurrence. CYP2C19 loss-of-function (LoF) polymorphism is assumed to be responsible for the poor metabolism of clopidogrel that ultimately turns to resistance. Previous publications could not provide firm evidence due to highly conflicting and heterogeneous outcomes. AIM: To get clear evidence from an updated meta-analysis on CYP2C19 LoF polymorphism association with stroke risk in clopidogrel treated patients, this study has been performed. METHODS: We conducted a meta-analysis with 72 selected studies from authentic databases, including 40,035 coronary artery disease patients treated with clopidogrel. RESULTS: This analysis showed that the worldwide carrier of one or more CYP2C19 LoF alleles had a significantly higher risk of stroke and composite events than the non-LoF carriers (RR=1.78, 95% CI=1.52-2.07, p<0.00001 and RR=1.39, 95% CI=1.26-1.54, p<0.00001, respectively). Besides, subgroup analysis showed that Asian CYP2C19 LoF carriers had a significantly increased risk of stroke (RR=1.91, 95% CI=1.60-2.28, p<0.00001) while the risk of composite events was significantly higher in all ethnic populations (Asian: RR=1.58, 95% CI=1.32-1.89, p<0.00001; Caucasian: RR=1.27, 95% CI=1.08-1.50, p=0.003; Hispanic and others: RR=1.21, 95% CI=1.09-1.34, p=0.0003). CONCLUSION: Our meta-analysis confirmed that the presence of CYP2C19 LoF alleles increases the risk of stroke and composite events recurrence in the worldwide population, especially in Asians undergoing clopidogrel treatment. Alternative antiplatelet therapy should be investigated thoroughly for the intermediate and poor metabolizers.


Assuntos
Doença da Artéria Coronariana , Acidente Vascular Cerebral , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Citocromo P-450 CYP2C19/genética , Grupos Étnicos , Genótipo , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Resultado do Tratamento
10.
Biomolecules ; 11(5)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065198

RESUMO

This study investigated the renin-angiotensin-aldosterone system (RAAS) gene polymorphisms as possible genetic risk factors for the restenosis development in patients with drug-eluting stents. 113 participants had coronary artery disease and underwent stenting. The control group consisted of 62 individuals with intact coronary arteries. Patients were divided into two groups: with in-stent restenosis (ISR) and without it. The patients with ISR were classified into subgroups by the terms of the restenosis development and age. Real-time PCR and Restriction Fragment Length Polymorphism-PCR were used to genotype the study participants for RAAS gene polymorphisms. We found that the development of restenosis is generally associated with the minor A allele for renin (REN) rs2368564 and the major TT genotype for angiotensinogen (AGT) rs699. The heterozygous genotype for AGT rs4762 acts as a protective marker. A minor A allele for angiotensin II type 2 receptor (AGTR2) rs1403543 is associated with a risk of restenosis in people under 65 years old. Among patients with the early ISR, heterozygotes for angiotensin II type 1 receptor (AGTR1) rs5186 are more frequent, as well as A allele carriers for AGTR2 rs1403543. A minor homozygous genotype for REN rs41317140 and heterozygous genotype for aldosterone synthase (CYP11B2) rs1799998 are predisposed to the late restenosis. Thus, to choose the effective treatment tactics for patients with coronary artery disease, it is necessary to genotype patients for the RAAS polymorphisms, which, along with age and clinical characteristics, will allow a comprehensive assessment of the risk of the restenosis development after stenting.


Assuntos
Doença da Artéria Coronariana/genética , Reestenose Coronária/etiologia , Stents Farmacológicos/efeitos adversos , Polimorfismo de Nucleotídeo Único , Sistema Renina-Angiotensina , Idoso , Angiotensinogênio/genética , Doença da Artéria Coronariana/complicações , Reestenose Coronária/genética , Citocromo P-450 CYP11B2/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Renina/genética
11.
Clin Biochem ; 95: 60-65, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34097878

RESUMO

OBJECTIVE: Coronary artery disease (CAD) as an important cause of morbidity and mortality globally. The scavenger receptor class B type 1 (SCARB1) plays an essential role in the reverse cholesterol transport. We have explored the association between a genetic variant, rs5888, in the SCARB1 gene with CAD and serum HDL-C levels. METHODS: Patients were categorized into two groups' angiogram positive (>50% coronary stenosis) and angiogram negative (<50% coronary stenosis). Genotyping was carried out using polymerase chain reaction-amplification refractory mutation system. The association between the SNP rs5888 and serum HDL-C was analyzed using a logistic regression model. RESULTS: The results showed that the subjects carrying a T allele was associated with a decreased serum HDL-C levels compared to the C allele in total population (p < 0.001). The risk of angiogram positivity in subjects carrying a T allele was 3.1-fold higher than for the control group (p < 0.001). CONCLUSION: CVD patients carrying the T allele of rs5888 variant in the SCARB1 gene was associated with decreased serum level of HDL.


Assuntos
Uso do Códon/genética , Doença da Artéria Coronariana/genética , Receptores Depuradores Classe B/genética , Adulto , Idoso , Estudos de Casos e Controles , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Receptores Depuradores Classe B/química
12.
Viruses ; 13(6)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071557

RESUMO

Patients with underlying cardiovascular conditions are particularly vulnerable to severe COVID-19. In this project, we aimed to characterize similarities in dysregulated immune pathways between COVID-19 patients and patients with cardiomyopathy, venous thromboembolism (VTE), or coronary artery disease (CAD). We hypothesized that these similarly dysregulated pathways may be critical to how cardiovascular diseases (CVDs) exacerbate COVID-19. To evaluate immune dysregulation in different diseases, we used four separate datasets, including RNA-sequencing data from human left ventricular cardiac muscle samples of patients with dilated or ischemic cardiomyopathy and healthy controls; RNA-sequencing data of whole blood samples from patients with single or recurrent event VTE and healthy controls; RNA-sequencing data of human peripheral blood mononuclear cells (PBMCs) from patients with and without obstructive CAD; and RNA-sequencing data of platelets from COVID-19 subjects and healthy controls. We found similar immune dysregulation profiles between patients with CVDs and COVID-19 patients. Interestingly, cardiomyopathy patients display the most similar immune landscape to COVID-19 patients. Additionally, COVID-19 patients experience greater upregulation of cytokine- and inflammasome-related genes than patients with CVDs. In all, patients with CVDs have a significant overlap of cytokine- and inflammasome-related gene expression profiles with that of COVID-19 patients, possibly explaining their greater vulnerability to severe COVID-19.


Assuntos
COVID-19/imunologia , COVID-19/fisiopatologia , Cardiomiopatias/imunologia , Doença da Artéria Coronariana/imunologia , Tromboembolia Venosa/imunologia , COVID-19/complicações , COVID-19/genética , Cardiomiopatias/complicações , Cardiomiopatias/genética , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Citocinas/genética , Conjuntos de Dados como Assunto , Humanos , Hospedeiro Imunocomprometido/genética , Inflamassomos/genética , Contagem de Linfócitos , Gravidade do Paciente , RNA-Seq , Tromboembolia Venosa/complicações
13.
Atherosclerosis ; 328: 33-37, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34082327

RESUMO

BACKGROUND AND AIMS: The APOE ε4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect modification of physical activity, oily fish and polyunsaturated fatty acid (PUFA) intake with APOE genotype on risk of incident CAD. METHODS: The present study comprised 345,659 white European participants from UK Biobank (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. RESULTS: Higher physical activity level and oily fish intake were both associated with a lower incidence of CAD. However, these associations were similar across the different APOE genotypes (p-values for interaction > 0.05). Most notable, higher PUFA intake was associated with a lower CAD risk in APOE ε4 genotype carriers (hazard ratio: 0.76, 95% confidence interval: 0.63-0.92), and not in APOE ε3/ε3 genotype carriers (0.90; 0.79, 1.02), but without statistical evidence for effect modification (p-valueinteraction = 0.137). CONCLUSIONS: While higher physical activity and high fish and PUFA intake were associated with a lower risk of incident CAD, no evidence for interaction of these lifestyle factors with APOE genotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE genotype carriers.


Assuntos
Doença da Artéria Coronariana , Animais , Apolipoproteínas E/genética , Bancos de Espécimes Biológicos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia
14.
Mutat Res Rev Mutat Res ; 787: 108348, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083055

RESUMO

Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Coronary angiography allows an accurate assessment of the extent and severity of atherosclerotic coronary narrowing, but it provides little characterization of early detection of potentially asymptomatic vulnerable plaque. The identification of the coronary "vulnerable patient" or high-risk plaques remains a major challenge in the treatment of CAD. Recently, growing evidence shows that DNA damage plays a role in the initiation and progression of atherosclerotic plaque. Cytokinesis-block micronucleus (CBMN) assay is one of the most frequently used and validated method for assessing chromosomal damage and genetic instability. Accordingly, the purpose of this systematic review was to retrieve and discuss existing literature on the studies assessing the association between MN and angiographically-proven CAD. A total of 8 studies published between 2001 and 2017 were included in the meta-analysis. Despite a large heterogeneity between studies (I2= 99.7 %, p < 0.0001), an overall increase of MN frequencies was found in patients with CAD compared with control group (meta-MR = 1.96; 95 % CI, 1.5-3.2, p = 0.009). A subgroup analysis showed an increase in the frequency of MN formation for both two- vessel (MR = 2.13, 95 % CI: 0.9-6.9, p = 0.08) and three-vessel disease (MR = 2.89, 95 % CI: 1.84-4.55, P = 0.06). Overall, the results of this meta-analysis provide evidence of an association between CBMN and presence, extent and severity of angiographically-assessed CAD. However, the small number of papers analyzed requires further large and more rigorously designed studies, carefully considering a series of clinical confounding factors, such as the quality of the metabolic control, the influence of drugs and radiation imaging treatments.


Assuntos
Doença da Artéria Coronariana/genética , Animais , Citocinese/genética , Citocinese/fisiologia , Dano ao DNA/genética , Dano ao DNA/fisiologia , Humanos , Micronúcleos com Defeito Cromossômico , Testes para Micronúcleos
16.
Hematology ; 26(1): 447-452, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34165031

RESUMO

BACKGROUND: Diabetes mellitus is a major factor in clopidogrel resistance (CR), and the glucokinase (GCK) gene plays a pivotal role in glucose homeostasis. This study investigated the contribution of GCK polymorphisms to CR risk. METHODS: Two hundred SCAD patients were recruited, and their platelet functions were detected by the Verify-Now P2Y12 assay. The polymorphisms of GCK were tested based on the methods of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We investigated the associations of GCK polymorphisms and CR. Multivariate logistic regression was performed to analyse the correlations between GCK polymorphisms and clinical values. RESULTS: Our study found that the SNPs rs4607517 and rs6975024 were associated with CR. Additionally, patients with the G allele of rs4607517had a greater CR risk, but the C allele of rs6975024 might be a protective factor. Finally, logistic regression revealed that CC + TC (rs6975024) as well as the values of albumin were correlated with a decreased risk of CR, and higher levels of uric acid (UA) may be positively associated with CR. CONCLUSION: The GCK gene polymorphisms might increase the CR risk in SCAD patients. Meanwhile, higher albumin levels and lower UA values might decrease the risk.


Assuntos
Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Resistência a Medicamentos , Glucoquinase/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único , Idoso , Clopidogrel/farmacologia , Doença da Artéria Coronariana/genética , Humanos , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacologia
17.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072943

RESUMO

Coronary artery disease remains one of the primary healthcare problems due to the high cost of treatment, increased number of patients, poor clinical outcomes, and lack of effective therapy. Though pharmacological and surgical treatments positively affect symptoms and arrest the disease progression, they generally exhibit a limited effect on the disease outcome. The development of alternative therapeutic approaches towards ischemic disease treatment, especially of decompensated forms, is therefore relevant. Therapeutic angiogenesis, stimulated by various cytokines, chemokines, and growth factors, provides the possibility of restoring functional blood flow in ischemic tissues, thereby ensuring the regeneration of the damaged area. In the current study, based on the clinically approved plasmid vector pVax1, multigenic constructs were developed encoding vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF2), and the DsRed fluorescent protein, integrated via picornaviruses' furin-2A peptide sequences. In vitro experiments demonstrated that genetically modified cells with engineered plasmid constructs expressed the target proteins. Overexpression of VEGF and FGF2 resulted in increased levels of the recombinant proteins. Concomitantly, these did not lead to a significant shift in the general secretory profile of modified HEK293T cells. Simultaneously, the secretome of genetically modified cells showed significant stimulating effects on the formation of capillary-like structures by HUVEC (endothelial cells) in vitro. Our results revealed that when the multicistronic multigene vectors encoding 2A peptide sequences are created, transient transgene co-expression is ensured. The results obtained indicated the mutual synergistic effects of the growth factors VEGF and FGF2 on the proliferation of endothelial cells in vitro. Thus, recombinant multicistronic multigenic constructs might serve as a promising approach for establishing safe and effective systems to treat ischemic diseases.


Assuntos
Doença da Artéria Coronariana/genética , Fator 2 de Crescimento de Fibroblastos/genética , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Indutores da Angiogênese/farmacologia , Proliferação de Células/genética , Doença da Artéria Coronariana/terapia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Furina/genética , Regulação da Expressão Gênica/genética , Genes/genética , Vetores Genéticos , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Patológica/terapia , Neovascularização Fisiológica/genética , Peptídeos/genética , Peptídeos/farmacologia , Plasmídeos/genética , Plasmídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia
18.
Arterioscler Thromb Vasc Biol ; 41(7): 2201-2214, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34039022
19.
BMJ Case Rep ; 14(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011640

RESUMO

Familial hypercholesterolaemia is a genetic disorder secondary to mutation of one or more of the genes critical for low-density lipoprotein cholesterol (LDL-C) metabolism; these mutation(s) cause highly elevated serum LDL-C, significantly increasing the risk of early cardiovascular events and mortality. Homozygous familial hypercholesterolaemia (HoFH) is rare and often leads to accelerated coronary atherosclerosis presenting within the first two decades of life. We report a case of a 14-year-old boy who presented after surviving a ventricular fibrillation cardiac arrest. His highly elevated LDL-C level prompted further workup and led to a diagnosis of HoFH. The treatment included medical therapy and coronary artery bypass grafting. The patient also required referral for lipid apheresis to meet goal LDL-C level, and an automated implantable cardioverter defibrillator for secondary prevention of sudden cardiac death. HoFH, if left untreated, can have devastating consequences Therefore, timely diagnosis initiating appropriate therapy is important.


Assuntos
Anticolesterolemiantes , Remoção de Componentes Sanguíneos , Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Adolescente , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol , Doença da Artéria Coronariana/genética , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Masculino
20.
Nutr Metab Cardiovasc Dis ; 31(6): 1832-1839, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33975736

RESUMO

BACKGROUND AND AIMS: Serum uric acid (SUA) levels have been reported to be associated with an increased risk of coronary artery disease (CAD) among patients with diabetes in observational study. Whether this relationship is causal remains unclear. The current study aimed to explore the causal association between SUA and the risk of CAD in patients with diabetes. METHODS AND RESULTS: A two-sample Mendelian randomization (MR) approach was employed to evaluate the causal effect of SUA on the risk of CAD in patients with diabetes. A total of 28 single nucleotide polymorphisms (SNPs) related to SUA were identified as instruments. Genetic association with CAD were obtained from a recently published genome-wide association study (GWAS) of 15,666 patients with diabetes (3968 CAD cases and 11,696 controls). The fixed-effects inverse variance-weighted method was employed to estimate the causal effect for the primary analysis, and other robust methods were employed for sensitivity analyses. In addition, the whole analyses were repeated using 9 non-pleiotropic SNPs. Genetic determined SUA levels were not significantly associated with the risk of CAD in patients with diabetes in the primary analysis (odds ratio = 1.13, 95% confidence interval: 0.98-1.16, P = 0.09). Consistent results were observed in the sensitivity analyses using various robust methods. In addition, this finding was confirmed by the repeated analyses using 9 non-pleiotropic SNPs. CONCLUSIONS: This two-sample MR study does not support a causal effect of genetically predicted SUA levels on the risk of CAD in patients with diabetes.


Assuntos
Doença da Artéria Coronariana/genética , Diabetes Mellitus/genética , Hiperuricemia/genética , Polimorfismo de Nucleotídeo Único , Ácido Úrico/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/diagnóstico , Diabetes Mellitus/diagnóstico , Estudo de Associação Genômica Ampla , Humanos , Hiperuricemia/sangue , Hiperuricemia/complicações , Hiperuricemia/diagnóstico , Análise da Randomização Mendeliana , Medição de Risco , Fatores de Risco , Regulação para Cima
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