RESUMO
Many studies have demonstrated the association of atrial fibrillation (AF) with endogenous genetic regulatory mechanisms. These interactions could advance the understanding of the AF pathophysiological process, supporting the search for early biomarkers to improve diagnosis and disease monitoring. Among the endogenous genetic regulatory mechanisms, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have gained special attention, and studies have demonstrated their involvement in AF development and other AF-related diseases such as coronary artery disease and cardiomyopathy. This review describes the main experimental results reported by studies that analyzed the expression of lncRNAs and circRNAs in AF associated with miRNA or mRNA. The search was conducted in PubMed public database using the terms "lncRNA and atrial fibrillation" or "long ncRNA and atrial fibrillation" or "long non-coding RNA and atrial fibrillation" or "circular RNA and atrial fibrillation" or "circRNA and atrial fibrillation". There was no overlapping of lncRNA or circRNA among the studies, attributed to the different sample types, methods, species, and patient classification evaluated in these studies. Although the regulatory mechanisms in which these molecules are involved are not yet well understood, the studies analyzed show their importance in the pathophysiological process of AF, supporting the idea that lncRNAs and circRNAs are involved in miRNA or mRNA regulation in the molecular mechanism of this disease.
Assuntos
Fibrilação Atrial , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Circular/genética , Fibrilação Atrial/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , RNA Mensageiro/genética , Redes Reguladoras de GenesRESUMO
JARID2 (Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. JARID2 acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes. JARID2 plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving JARID2. For this study, our aim was to determine whether patients with larger deletions spanning beyond JARID2 present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22-p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic JARID2 variants or patients carrying copy number variants, and three patients with JARID2 VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the JARID2-neurodevelopmental syndrome. DNA methylation analysis indicated that JARID2 is the driver gene for aberrant DNA methylation observed in 6p22-p24 microdeletions. In addition, we performed analysis of functional correlation of the JARID2 genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the JARID2 episignature in 6p22-p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by JARID2 is lost.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Genômica , Transtornos do Neurodesenvolvimento/genética , Epigenoma , Deficiência Intelectual/genética , Epigenômica , Complexo Repressor Polycomb 2/genéticaRESUMO
Heart failure (HF) is a clinical syndrome that involves structural changes in the heart, leading to a decrease in cardiac output, mainly caused by myocardial infarction (MI), which is the most common form of cardiovascular disease worldwide. Clinical evaluation remains the most accurate diagnostic method for ischemic HF, since the known biomarkers have high cost, are difficult to use for early diagnosis, and have low specificity. This often leads to late diagnosis since only ~ 25% symptoms of HF appear after MI. Studies suggest that small non-coding RNAs (miRNAs) play an important role in the regulation of this pathophysiological process and are, therefore, important targets in the discovery of non-invasive biomarkers for HF. Thus, the aim of this review was to identify circulating miRNAs (plasma, serum, and whole blood) described for post-MI HF patients. This review covered 19 experimental studies on humans, which investigated the relationship between circulating miRNAs and the development, monitoring, or prognosis of ischemic HF. This analysis was aimed at proposing potential targets for HF and the future application of miRNAs as HF biomarkers.
Assuntos
Insuficiência Cardíaca/sangue , MicroRNAs/sangue , Infarto do Miocárdio/complicações , Biomarcadores/sangue , Insuficiência Cardíaca/etiologia , Humanos , Infarto do Miocárdio/sangue , PrognósticoRESUMO
BACKGROUND: MicroRNAs (miRNAs) are involved in the pathogenesis of atrial fibrillation (AF), acting on development and progression. Our pilot study investigated the expression of six miRNAs and their miRNA-mRNA interactions in patients with acute new-onset AF, well-controlled AF, and normal sinus rhythm (controls). METHODS AND RESULTS: Plasma of acute new-onset AF patients (n = 5) was collected in the emergency room when patients presented with irregular and fast-atrial fibrillation rhythm. Samples from well-controlled AF (n = 16) and control (n = 15) patients were collected during medical appointments following an ECG. Expression of miR-21, miR-133a, miR-133b, miR-150, miR-328, and miR-499 was analyzed by real-time PCR. Ingenuity Pathway Analysis and the TargetScan database identified the top 30 mRNA targets of these miRNA, seeking the miRNA-mRNA interactions in cardiovascular process. Increased expression of miR-133b (1.4-fold), miR-328 (2.0-fold), and miR-499 (2.3-fold) was observed in patients with acute new-onset AF, compared with well-controlled AF and control patients. Decreased expression of miR-21 was seen in patients with well-controlled AF compared to those with acute new-onset AF and controls (0.6-fold). The miRNA-mRNA interaction demonstrated that SMAD7 and FASLG genes were the targets of miR-21, miR-133b, and miR-499 and were directly related to AF, being involved in apoptosis and fibrosis. CONCLUSION: The miRNAs had different expression profiles dependent on the AF condition, with higher expression in the acute new-onset AF than well-controlled AF. Clinically, this may contribute to an effective assessment for patients, leading to early detection of AF and monitoring to reduce the risk of other serious cardiovascular events.
Assuntos
Fibrilação Atrial/sangue , MicroRNA Circulante/sangue , Redes Reguladoras de Genes/fisiologia , RNA Mensageiro/sangue , Doença Aguda , Adulto , Idoso , Fibrilação Atrial/genética , MicroRNA Circulante/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Thyroid cancer is a common malignant disease of the endocrine system with increasing incidence rates over the last few decades. In this study, we sought to analyze the possible association of 45 single nucleotide polymorphisms (SNPs) with thyroid cancer in a population from Rio Grande do Norte, Brazil. METHODS: Based on histological analysis by a pathologist, 80 normal thyroid specimens of tissue adjacent to thyroid tumors were obtained from the biobank at the Laboratory of Pathology of Liga Norte Riograndense Contra o Câncer, Natal, RN. Patient samples were then genotyped using the MassARRAY platform (Sequenon, Inc) followed by statistical analysis employing the SNPassoc package in R program. The genotypic frequencies of all 45 SNPs obtained from the International HapMap Project database and based on data from the ancestral populations of European and African origin were used to compose the control study group. RESULTS: In our study, the following 9 SNPs showed significant differences in their frequency when comparing the study and control groups: rs3744962, rs258107, rs1461855, rs4075022, rs9943744, rs4075570, rs2356508, rs17485896, and rs2651339. Furthermore, the SNPs rs374492 C/T and rs258107 C/T were associated with a relative risk for thyroid carcinoma of 3.78 (p = 6.27 × 10e-5) and 2.91 (p = 8.27 × 10e-5), respectively, after Bonferroni's correction for multiple comparisons. CONCLUSIONS: These nine polymorphisms could be potential biomarkers of predisposition to thyroid carcinoma in the population from Rio Grande do Norte. However, complementary studies including a control group with samples obtained from healthy subjects in Rio Grande do Norte state, should be conducted to confirm these results.
Assuntos
Estudos de Associação Genética/métodos , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/genética , Adulto , Brasil , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Projetos Piloto , Estudos RetrospectivosRESUMO
Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Genetics analysis has established electrophysiological substrates, which determine individual vulnerability to AF occurrence and maintenance. MicroRNAs (miRNAs) found in virtually all organisms function as negative regulators of protein-coding genes. Several studies have suggested a role for miRNAs in the regulation of cardiac excitability and arrhythmogenesis. This review is based on 18 studies conducted between 2009 and 2013 to investigate the association of miRNAs with AF. miRNAs are discussed here as candidate biomarkers for AF in blood and cardiac tissues and as potential targets for AF therapy.
Assuntos
Fibrilação Atrial/metabolismo , Biomarcadores/metabolismo , MicroRNAs/metabolismo , Fibrilação Atrial/complicações , Remodelamento Atrial , Biomarcadores/sangue , Humanos , MicroRNAs/sangueRESUMO
8q21.11 microdeletions encompassing the gene encoding transcription factor ZFHX4, have previously been associated by us with a syndromic form of intellectual disability, hypotonia, decreased balance and hearing loss. Here, we report on 57 individuals, 52 probands and 5 affected family members, with protein truncating variants (n=36), (micro)deletions (n=20) or an inversion (n=1) affecting ZFHX4 with variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions and ZFHX4 intragenic loss-of-function variants largely overlap, identifying ZFHX4 as the main driver for the microdeletion syndrome, although leukocyte-derived DNA shows a mild common methylation profile for (micro)deletions only. We identify ZFHX4 as a transcription factor that is increasingly expressed during human brain development and neuronal differentiation. Furthermore, ZFHX4 interacting factors identified via IP-MS in neural progenitor cells, suggest an important role for ZFHX4 in cellular and developmental pathways, especially during histone modifications, cytosolic transport and development. Additionally, using CUT&RUN, we observed that ZFHX4 binds with the promoter regions of genes with crucial roles in embryonic, neuron and axon development. Since loss-of-function variants in ZFHX4 are found with consistent dysmorphic facial features, we investigated whether the disruption of zfhx4 causes craniofacial abnormalities in zebrafish. First-generation (F0) zfhx4 crispant zebrafish, (mosaic) mutant for zfhx4 loss-of-function variants, have significantly shorter Meckel's cartilages and smaller ethmoid plates compared to control zebrafish. Furthermore, behavioral assays show a decreased movement frequency in the zfhx4 crispant zebrafish in comparison with control zebrafish larvae. Although further research is needed, our in vivo work suggests a role for zfhx4 in facial skeleton patterning, palatal development and behavior.
RESUMO
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by pathogenic variants in TCF4, leading to intellectual disability, specific morphological features, and autonomic nervous system dysfunction. Epigenetic dysregulation has been implicated in PTHS, prompting the investigation of a DNA methylation (DNAm) "episignature" specific to PTHS for diagnostic purposes and variant reclassification and functional insights into the molecular pathophysiology of this disorder. A cohort of 67 individuals with genetically confirmed PTHS and three individuals with intellectual disability and a variant of uncertain significance (VUS) in TCF4 were studied. The DNAm episignature was developed with an Infinium Methylation EPIC BeadChip array analysis using peripheral blood cells. Support vector machine (SVM) modeling and clustering methods were employed to generate a DNAm classifier for PTHS. Validation was extended to an additional cohort of 11 individuals with PTHS. The episignature was assessed in relation to other neurodevelopmental disorders and its specificity was examined. A specific DNAm episignature for PTHS was established. The classifier exhibited high sensitivity for TCF4 haploinsufficiency and missense variants in the basic-helix-loop-helix domain. Notably, seven individuals with TCF4 variants exhibited negative episignatures, suggesting complexities related to mosaicism, genetic factors, and environmental influences. The episignature displayed degrees of overlap with other related disorders and biological pathways. This study defines a DNAm episignature for TCF4-related PTHS, enabling improved diagnostic accuracy and VUS reclassification. The finding that some cases scored negatively underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants.
Assuntos
Metilação de DNA , Hiperventilação , Deficiência Intelectual , Fator de Transcrição 4 , Humanos , Fator de Transcrição 4/genética , Hiperventilação/genética , Hiperventilação/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Feminino , Masculino , Criança , Fácies , Adolescente , Epigenômica/métodos , Epigênese Genética , Hipercinese/genética , Pré-Escolar , Adulto , Adulto JovemRESUMO
Members of the triggering receptor expressed on myeloid cells (TREM) family are associated with atherosclerosis risk and progression. TREML4 is upregulated in the early phase of acute coronary syndrome. We investigated the relationship between the mRNA expression of 13 genes in blood leukocytes, TREML4 polymorphisms, and coronary artery lesion extension (Friesinger index) in patients with coronary artery disease (CAD) (n = 137). TREML4 rs2803495 (A > G) and rs2803496 (T > C) variants and leukocyte mRNA expression were analysed by qRT-PCR. TREML4 expression was higher in patients with major coronary artery lesions than in subjects without or with low and intermediate lesions (p < 0.05). However, TREML4 polymorphisms were not associated with coronary lesion extent. Presence of the rs2803495 G allele was not associated with increased TREML4 mRNA expression. Patients carrying the rs2803496 C allele (TC/CC genotypes) were more likely to express TREML4 mRNA than non-C allele carriers (allele C: OR 7.3, and 95% CI 1.9-27.5, p = 0.03). In conclusion, increased TREML4 mRNA expression in blood leukocytes is influenced by gene polymorphisms and is associated with more severe coronary artery lesions, suggesting its potential as a biomarker of the extent of coronary lesions in patients with CAD.
Assuntos
Doença da Artéria Coronariana/diagnóstico , Leucócitos/metabolismo , RNA Mensageiro/metabolismo , Receptores Imunológicos/genética , Adulto , Idoso , Alelos , Aterosclerose/complicações , Aterosclerose/patologia , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Leucócitos/citologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/metabolismoRESUMO
OBJECTIVES: Inflammatory molecules play a role in the development of atherosclerosis, which is the primary origin of cardiovascular disorders. However, to the best of our knowledge, no study has attempted to investigate the relationship between these circulating molecules and the prediction of cardiovascular risk. The present study aimed to investigate the relationships of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and matrix metalloproteinase 9 serum concentrations with the extent of coronary lesions. METHODS: Seventy-four individuals who were undergoing coronary angiography for the first time for diagnostic purposes were enrolled in this study. The extent of the coronary lesion was assessed using the Friesinger Index, and subjects were classified into four groups: no lesions, minor lesions, intermediate lesions and major lesions. Serum biochemical parameters and serum concentrations of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and matrix metalloproteinase 9 were analyzed. RESULTS: The vascular cell adhesion molecule-1 concentration was higher than 876 ng/mL in individuals with intermediate and major lesions (p<0.001 and p=0.020, respectively). Moreover, logistic regression analysis showed that these patients had an increased risk of having an intermediate lesion (p=0.007). Interestingly, all individuals with major lesions had vascular cell adhesion molecule-1 concentrations higher than 876 ng/mL. No association was found between the concentrations of the other proteins and the Friesinger Index. CONCLUSIONS: Serum vascular cell adhesion molecule-1 may be associated with the extent of coronary lesions. Moreover, it may represent an alternative to improve the cardiovascular risk classification in patients without acute coronary syndrome.
Assuntos
Doença da Artéria Coronariana/sangue , Selectina E/sangue , Molécula 1 de Adesão Intercelular/sangue , Metaloproteinase 9 da Matriz/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Adulto , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico , Prognóstico , Índice de Gravidade de DoençaRESUMO
Atrial fibrillation (AF) is the most common supraventricular arrhythmia in the population. MicroRNAs (small endogenous noncoding RNAs) are attractive candidates as biomarkers for AF, especially considering that miRNAs are stable and are detected within easily accessible biofluids such as blood. In this review, we selected twelve studies (2012 to 2016) that were classified according to the sample type. We aimed to provide an overview of the role of circulating miRNAs in AF and to discuss the variability of the results, seeking to improve the perspective of the use of miRNAs as potential noninvasive biomarkers for this heart disease.
Assuntos
Fibrilação Atrial/sangue , Biomarcadores/sangue , MicroRNAs/sangue , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Humanos , MicroRNAs/genéticaRESUMO
OBJECTIVES: Inflammatory molecules play a role in the development of atherosclerosis, which is the primary origin of cardiovascular disorders. However, to the best of our knowledge, no study has attempted to investigate the relationship between these circulating molecules and the prediction of cardiovascular risk. The present study aimed to investigate the relationships of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and matrix metalloproteinase 9 serum concentrations with the extent of coronary lesions. METHODS: Seventy-four individuals who were undergoing coronary angiography for the first time for diagnostic purposes were enrolled in this study. The extent of the coronary lesion was assessed using the Friesinger Index, and subjects were classified into four groups: no lesions, minor lesions, intermediate lesions and major lesions. Serum biochemical parameters and serum concentrations of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and matrix metalloproteinase 9 were analyzed. RESULTS: The vascular cell adhesion molecule-1 concentration was higher than 876 ng/mL in individuals with intermediate and major lesions (p<0.001 and p=0.020, respectively). Moreover, logistic regression analysis showed that these patients had an increased risk of having an intermediate lesion (p=0.007). Interestingly, all individuals with major lesions had vascular cell adhesion molecule-1 concentrations higher than 876 ng/mL. No association was found between the concentrations of the other proteins and the Friesinger Index. CONCLUSIONS: Serum vascular cell adhesion molecule-1 may be associated with the extent of coronary lesions. Moreover, it may represent an alternative to improve the cardiovascular risk classification in patients without acute coronary syndrome.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Doença da Artéria Coronariana/sangue , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Selectina E/sangue , Metaloproteinase 9 da Matriz/sangue , Prognóstico , Índice de Gravidade de Doença , Doença da Artéria Coronariana/patologia , Biomarcadores/sangue , Placa Aterosclerótica/diagnósticoRESUMO
ABSTRACT Chronic kidney disease (CKD) increases cardiovascular disease (CVD) risk development. However, the mechanisms of reduced kidney function with CVD risk are unclear. This study aimed to investigate the association between kidney function and Framingham risk score (FRS) in participants with traditional cardiovascular risk factors and normal estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m² in an admixed population of Brazil. The participants were divided into three groups according to FRS: low risk group with 0% to <10%, moderate risk group with ≥10% to 20% and high risk group with >20%. The eGFR was calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Data from participants were collected by questionnaire, and blood and urine samples were collected to analyze biochemical markers. A total of 214 subjects aged 53±10 years old was collected. There were 77 individuals in low risk group, 59 in moderate risk group and 78 in high-risk group. Mean eGFRCKD-EPI was 89.39±15.05 mL/min/1.73 m² and 90.74±16.17 mL/min/1.73 m2 when race adjustment. The results indicated that there is an increasing the cardiovascular risk with a decreased of eGFR, conforming to a significant inverse correlation observed between eGFR and FRS with Spearman correlation (R²=-0.256, p<0.001; R²=-0.224, p=0.001, when adjusted for race). There was a statistically significant difference in eGFRCKD-EPI (p<0.001) and eGFRCKD-EPI with race adjustment (p=0.002) among risk groups. The data suggests that the reduction eGFR is associated with elevated FRS among Brazilian adults without CKD. Furthermore, the results suggest that race adjustment it's not necessary in Brazilian population.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Insuficiência Renal Crônica/complicações , Doenças Cardiovasculares/complicações , Estatística como Assunto , Taxa de Filtração GlomerularRESUMO
A obtenção de um material genético íntegro e com concentrações satisfatórias para a amplificação de de uma determinada sequência são os principais desafios para o processamento de amostras de tecido preservados em parafina. O presente estudo teve como objetivo comparar três diferentes protocolos de extração de DNA que têm em comum entre si o princípio de extração por silica-gel. Vinte e sete amostras de tecidos tireoidianos preservados em parafina foram processadas por meio de cortes em triplicata de 20um. O método A utilizou tr~es horas na etapa de digestão do tecido, os métodos B e C utilizaram 16 horas para a digestão, sendo que o último utilizou diferentes solventes para reidratar o tecido e solução de fenol-clorofórmio-álcool isoamílico para purificação. Todos os métodos utilizaram em comum o conjunto de reagentes QIAamp DNA mini kit. Na comparação entre as concentrações obtidas de DNA, o método B spresentou maior média (3,7 ng/iL) já o método A obteve valor médio que 1,2 ng/uL e o método C, de 0,7 ng/uL. Todos os protocolos obtiveram valores da relação 260/280 e 260/230 fora dos valores de refer~encia esperado, evidenciando uma perda na qualidade do DNA extraído. O resultado da integridade do DNA, por meio de eletroforese em gel agarose também demonstrou o alto grau de degradação de todos os métodos analisados. Entretanto, foi possível realizar a genotipagem do polimorfismo 174G>C do gene da interleucina 6 em 100% das amostras testadas para o método C, e 66% par a o método A e B. O método C foi o mais reprodutivo para genotipagem , apesar do maior custo e tempo de processamento, sendo este método mais indicado para a implementação na rotina laboratorial de biologia molecular para amostras preservadas em parafina.