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OBJECTIVE: To evaluate the frequency and severity of various clinical symptoms of Parkinson's disease (PD) depending on the BDNF rs6265 polymorphism. MATERIAL AND METHODS: The study included 533 patients with PD. The stage of PD was assessed using the Hoehn and Yahr scale (1967), motor symptoms were evaluated with MDS-UPDRS. Assessment of non-motor symptoms (NMS) in PD was conducted using the Beck Depression Inventory II (BDI-II); the Hospital Anxiety and Depression Scale (HADS); the Apathy Scale; the Montreal Cognitive Assessment (MoCA test); the Questionnaire for Impulsive-Compulsive Disorders in PD -Rating Scale (QUIP-RS). Genotyping of the BDNF variant (rs6265) was performed using real-time PCR with TaqMan probes. RESULTS: Most PD patients have a combination of NMS increasing as the disease progresses and is determined by molecular-genetic individual characteristics. There are significant differences in the severity of motor symptoms and NMS: individuals with the AA genotype showed significantly pronounced motor symptoms (p<0.0001); emotional-affective symptoms (p<0.0001); cognitive and impulsive behavioral disorders (p<0.0001). CONCLUSION: The rs6265 BDNF allele A is associated with a wide range of NMS, increasing the risk of their development in patients with PD, thus playing the important role in the etiopathogenesis of this pathology.
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Factor Neurotrófico Derivado del Encéfalo , Enfermedad de Parkinson , Polimorfismo de Nucleótido Simple , Humanos , Factor Neurotrófico Derivado del Encéfalo/genética , Enfermedad de Parkinson/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Genotipo , Índice de Severidad de la Enfermedad , Depresión/genéticaRESUMEN
OBJECTIVE: To evaluate the clinical features and the level of serum brain-derived neurotrophic factor (BDNF) in groups of patients with Parkinson's disease (PD) differentiated by the genotypes of BDNF polymorphism (rs6265). MATERIAL AND METHODS: The level of serum BDNF in the biomarkers' multiplex panel of neurodegenerative diseases (HNDG3MAG-36K) was assessed in 134 PD patients. Allele discrimination was carried out by real-time PCR using TaqMan probes for the analysis of BDNF rs6265 polymorphism in groups of patients and controls (n=192) matched for sex, age and ethnicity. RESULTS: Comparing the distribution of rs6265 genotypes and alleles between groups of patients and controls no significant differences were found (p>0.05). Serum BDNF levels varied significantly by genotype (rs6265) among PD patients. Minimum mean serum BDNF level (320.1±164.6 pg/ml) was noted for individuals with the AA genotype, which significantly differs from the corresponding indicator among individuals with GA (2944.2±1590.6 pg/ml; p=0.0001) and GG genotypes (2949.4±1620.6 pg/ml; p=3.9×10-5). The concentration of BDNF significantly differed between patients with different forms of PD (p=0.0007) and increased as the stage of the disease progressed according to Hoehn and Yahr staging scale (p=1.0×10-6). CONCLUSION: The BDNF rs6265 polymorphism was not associated with the development of PD in the studied population. The variability of the mean serum BDNF level was established depending on the genotype of the BDNF polymorphism in PD patients and a number of clinical features.
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Factor Neurotrófico Derivado del Encéfalo , Enfermedad de Parkinson , Humanos , Alelos , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/genética , Etnicidad , Genotipo , Enfermedad de Parkinson/genéticaRESUMEN
The status of DNA methylation in the human genome changes during the pathogenesis of common diseases and acts as a predictor of life expectancy. Therefore, it is of interest to investigate the methylation level of regulatory regions of genes responsible for general biological processes that are potentially significant for the development of age-associated diseases. Among them there are genes encoding proteins of DNA repair system, which are characterized by pleiotropic effects. Here, results of the targeted methylation analysis of two regions of the human genome (the promoter of the MLH1 gene and the enhancer near the ATM gene) in different tissues of patients with carotid atherosclerosis are present. Analysis of the methylation profiles of studied genes in various tissues of the same individuals demonstrated marked differences between leukocytes and tissues of the vascular wall. Differences in methylation levels between normal and atherosclerotic tissues of the carotid arteries were revealed only for two studied CpG sites (chr11:108089866 and chr11:108090020, GRCh37/hg19 assembly) in the ATM gene. Based on this, we can assume the involvement of ATM in the development of atherosclerosis. "Overload" of the studied regions with transcription factor binding sites (according to ReMapp2022 data) indicate that the tissue-specific nature of methylation of the regulatory regions of the MLH1 and ATM may be associated with expression levels of these genes in a particular tissue. It has been shown that inter-individual differences in the methylation levels of CpG sites are associated with sufficiently distant nucleotide substitutions.
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Aterosclerosis , Enfermedades de las Arterias Carótidas , Humanos , Islas de CpG/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Metilación de ADN , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Enfermedades de las Arterias Carótidas/genética , Reparación del ADN/genéticaRESUMEN
miRNAs are vital molecules of gene expression. They are involved in the pathogenesis of various common diseases, including atherosclerosis, its risk factors, and its complications. A detailed characterization of the spectrum of functionally significant polymorphisms of miRNA genes in patients with advanced carotid atherosclerosis is an important research task. We analyzed miRNA expression and exome sequencing data of carotid atherosclerotic plaques of male patients (n = 8, 66-71 years of age, 67-90% degree of carotid artery stenosis). For further study and analysis of the association between the rs2910164 polymorphism of the MIR146A gene and advanced carotid atherosclerosis, we recruited 112 patients and 72 relatively healthy Slavic residents of Western Siberia. A total of 321 and 97 single nucleotide variants (SNVs) were detected in the nucleotide sequences of pre- and mature miRNAs in carotid atherosclerotic plaques. These variants were located in 206 and 76 miRNA genes, respectively. Integration of the data of exome sequencing and miRNA expression revealed 24 SNVs of 18 miRNA genes that were processed to mature form in carotid atherosclerotic plaques. SNVs with the greatest potential functional significance for miRNA expression predicted in silico were rs2910164:C>G (MIR146A), rs2682818:A>C (MIR618), rs3746444:A>G (MIR499A), rs776722712:C>T (MIR186), rs199822597:G>A (MIR363). The expression of miR-618 was lower in carotid atherosclerotic plaques of patients with the AC rs2682818 genotype of the MIR618 gene compared with the CC genotype (log2FC = 4.8; p = 0.012). We also found an association of rs2910164:C (MIR146A) with the risk of advanced carotid atherosclerosis (OR = 2.35; 95% CI: 1.43-3.85; p = 0.001). Integrative analysis of polymorphisms in miRNA genes and miRNA expression is informative for identifying functionally significant polymorphisms in miRNA genes. The rs2682818:A>C (MIR618) is a candidate for regulating miRNA expression in carotid atherosclerotic plaques. The rs2910164:C (MIR146A) is associated with the risk of advanced carotid atherosclerosis.
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Enfermedades de las Arterias Carótidas , MicroARNs , Placa Aterosclerótica , Humanos , Masculino , Anciano , Placa Aterosclerótica/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , MicroARNs/genética , Enfermedades de las Arterias Carótidas/genéticaRESUMEN
In this study we compared methylation levels of 27,578 CpG sites between paired samples of the tumor and surrounding liver tissues with various degrees of damage (fibrosis, cirrhosis) in HCV-induced hepatocellular carcinoma (HCC) patients, as well as between tumor and normal tissue in non-viral HCC patients, using GSE73003 and GSE37988 data from GEODataSets (https://www.ncbi.nlm.nih.gov/). A significantly lower number of differentially methylated sites (DMS) were found between HCC of non-viral etiology and normal liver tissue, as well as between HCC and fibrosis (32 and 40), than between HCC and cirrhosis (2450 and 2304, respectively, according to GSE73003 and GSE37988 datasets). As the pathological changes in the tissue surrounding the tumor progress, the ratio of hyper-/hypomethylated DMSs in the tumor decreases. Thus, in tumor tissues compared with normal/fibrosis/cirrhosis of the liver, 75/62.5/47.7 % (GSE73003) and 16 % (GSE37988) of CpG sites are hypermethylated, respectively. Persistent hypermethylation of the ZNF154 and ZNF540 genes, as well as CCL20 hypomethylation, were registered in tumor tissue in relation to both liver fibrosis and liver cirrhosis. Protein products of the EDG4, CCL20, GPR109A, and GRM8 genes, whose CpG sites are characterized by changes in DNA methylation level in tumor tissue in the setting of cirrhosis and fibrosis, belong to "Signaling by G-protein-coupled receptors (GPCRs)" category. However, changes in the methylation level of the "driver" genes for oncopathology (ÐРС, CDKN2B, GSTP1, ELF4, TERT, WT1) are registered in tumor tissue in the setting of liver cirrhosis but not fibrosis. Among the genes hypermethylated in tumor tissue in the setting of liver cirrhosis, the most represented biological pathways are developmental processes, cell-cell signaling, transcription regulation, Wnt-protein binding. Genes hypomethylated in liver tumor tissue in the setting of liver cirrhosis are related to olfactory signal transduction, neuroactive ligand-receptor interaction, keratinization, immune response, inhibition of serine proteases, and zinc metabolism. The genes hypermethylated in the tumor are located at the 7p15.2 locus in the HOXA cluster region, and the hypomethylated CpG sites occupy extended regions of the genome in the gene clusters of olfactory receptors (11p15.4), keratin and keratin-associated proteins (12q13.13, 17q21.2, and 21q22.11), epidermal differentiation complex (1q21.3), and immune system function loci 9p21.3 (IFNA, IFNB1, IFNW1 cluster) and 19q13.41-19q13.42 (KLK, SIGLEC, LILR, KIR clusters). Among the genes of fibrogenesis or DNA repair, cg14143055 (ADAMDEC1) is located in the binding region of the HOX gene family transcription factors (TFs), while cg05921699 (CD79A), cg06196379 (TREM1) and cg10990993 (MLH1) are located in the binding region of the ZNF protein family transcription factor (TF). Thus, the DNA methylation profile in the liver in HCV-induced HCC is unique and differs depending on the degree of surrounding tissue lesion - liver fibrosis or liver cirrhosis.
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Genetic factors underlie the pathological processes that cause the manifestation of a wide range of neurodegenerative diseases. The pathological expansion of unstable trinucleotide repeats is known to lead monogenic neurological diseases such as Huntington's disease, Kennedy's disease, spinocerebellar ataxia, and others. However, the latest data suggests individuals with intermediate allele (IA) repeat length have a risk of developing common neurological phenotype, for example, Parkinson's disease, Alzheimer's disease. In this study, we review the current knowledge on intermediate alleles of HTT gene for pathogenesis and clinical features of neurodegenerative diseases, with the focus on Parkinson's disease. Early diagnosis of neurodegenerative disease and genetic counselling of the family can be improved via the implementation of specific management strategies of IA carriers by team of highly experienced professionals in the fields of neurology and genetics.
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Enfermedad de Huntington , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Alelos , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/genética , Enfermedad de Parkinson/genética , Expansión de Repetición de Trinucleótido , Repeticiones de Trinucleótidos/genéticaRESUMEN
Dysregulation of microRNA (miRNA) expression is associated with a susceptibility to many diseases, including atherosclerotic lesions of the coronary and carotid arteries and the development of clinical complications such as coronary heart disease, myocardial infarction, chronic cerebral ischemia, ischemic stroke. Recently, more and more studies analyze the miRNA regulome including a network of regulatory elements for the expression of miRNAs themselves and targets under their control. The review summarizes the data from articles concerned miRNA expression and changes in DNA methylation in the miRNA genes in human atherosclerotic arteries, as well as with the analysis of the association between single nucleotide polymorphisms and copy number variations in the miRNA genes with clinical complications of atherosclerosis.
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Aterosclerosis , Isquemia Encefálica , MicroARNs , Aterosclerosis/genética , Isquemia Encefálica/genética , Variaciones en el Número de Copia de ADN , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include microRNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs. Supplementary Information: The online version contains supplementary material available at 10.1134/S0026893322010034.
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The pandemic of coronavirus disease 2019 (COVID-19) warrants the identification of factors that may determine both risk and severity of infection. The factors include micro RNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs.
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COVID-19 , MicroARNs , COVID-19/genética , Humanos , MicroARNs/genética , Proteínas de Unión al ARN , SARS-CoV-2RESUMEN
In 2019, the SARS-CoV-2 beta-coronavirus, which caused a pandemic of severe acute respiratory viral infection COVID-19 (from COronaVIrus Disease 2019), was first detected. The susceptibility to SARS-CoV-2 and the nature of the course of the COVID-19 clinical picture are determined by many factors, including genetic characteristics of both the pathogen and the human. The SARS-CoV-2 genome has a similarity to the genomes of other coronaviruses, which are pathogenic for humans and cause a severe course of infection: 79% to the SARS-CoV genome and 50% to the MERS-CoV genome. The most significant differences between SARS-CoV-2 and other coronaviruses are recorded in the structure of the gene of the S protein, a key protein responsible for the virus binding to the receptor of the host organism cells. In particular, substitutions in the S protein of SARS-CoV-2, leading to the formation of the furin cleavage site that is absent in other SARS-like coronaviruses, were identified, which may explain the high pathogenicity of SARS-CoV-2. In humans, the genes that are significant for the initial stages of infection include ACE2, ANPEP, DPP4 (encode receptors for coronavirus binding); TMPRSS2, FURIN, TMPRSS11D, CTSL, CTSB (encode proteases involved in the entry of the coronavirus into the cell); DDX1 (the gene of ATP-dependent RNA helicase DDX1, which promotes replication of coronaviruses); and IFITM1, IFITM2, and IFITM3 (encode interferon-induced transmembrane proteins with an antiviral effect). These genes are expressed in many tissues (including those susceptible to the effects of SARS-CoV-2); rare and frequent variants that affect the structure of the encoded protein and its properties and expression level are described in them. A number of common genetic variants with proven functional significance are characterized by the variability in the allele frequency in the world's populations, which can determine interpopulation differences in the prevalence of COVID-19 and in the clinical features of the course of this pathology. The expression level of genes that are important for the formation of the susceptibility to SARS-CoV-2 is affected by epigenetic modifications, comorbidities at the time of infection, taking medications, and bad habits.
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Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) of TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) was estimated in the Slavs of West Siberia. We further investigated an association of SNPs in TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461), and ABTB2/ СÐТ (rs2022318) genes with bronchial asthma (BA), arterial hypertension (AH) and their comorbidity. Then, the disease-associated SNPs were annotated in silico in relation to their potential regulatory functions. Strong LD was detected between rs1928298 and rs1927914, as well as rs7026297 and rs7038716 in the Slavs of West Siberia. It was found that the rs1927914 G allele of the TLR4 gene and the rs1980616 C allele of the SERPINA1 gene are associated with the predisposition to BA. These SNPs can affect binding affinity of transcription factors of the Pou and Klf4 families, as well as the expression levels of the TLR4 and SERPINA1 genes. The rs11065987 allele A of the ATXN2/BRAP genes, the rs11669386 A allele of the CARD8 gene, the rs2284033 allele G of the IL2RB gene, and the rs11191582 allele G of the NT5C2 gene were associated with the risk of AH. These variants can alter binding affinity of the Hoxa9, Irf, RORalpha1 and HMG-IY transcription factors, as well as the expression levels of the ALDH2, CARD8, NT5C2, ARL3, and SFXN2 genes in blood cells/vessels/heart, respectively. The risk of developing a comorbid phenotype of AD and AH is associated with the A allele of rs7038716 and the T allele of rs7025144 of the TLR4/AL160272.2 genes, the A allele of rs1010461 of the ANG gene and the C allele of rs2022318 of the ABTB2/CAT genes. Variants rs7038716 and rs7025144 can change the expression levels of the TLR4 gene in blood cells, while rs1010461 and rs2022318 influence the expression levels of the ANG and RNASE4 genes as well as the CAT and ABTB2 genes in blood cells, lungs/vessels/heart.
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The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).
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Predisposición Genética a la Enfermedad , Infarto del Miocardio/genética , Genotipo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
In this study we performed a comparative gene expression analysis of carotid arteries in the area of atherosclerotic plaques and healthy internal mammary arteries of patients with advanced atherosclerosis by using microarray HumanHT-12 BeadChip ("Illumina"). The most down-regulated genes were APOD, FABP4, CIDEC and FOSB, and up-regulated gene was SPP1 (|FC|>64; pFDR<0.05). The majority of differentially expressed genes were down-regulated in advanced atherosclerotic plaques. Unexpectedly, genes involved in immune and inflammatory responses were down-regulated in advanced atherosclerotic plaques to compare with the healthy arteries (arachidonic acid metabolism, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, Jak-STAT signaling pathway, TNF signaling pathway). "Cellular response to metal ion" (metallothioneins) and "Extracellular matrix organization" were the most significant Gene ontology terms among the down- and up-regulated genes, respectively.
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Aterosclerosis , Placa Aterosclerótica , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Transducción de SeñalRESUMEN
This review provides modern data on the spectrum and the functional significance of micro-RNAs involved in atherogenesis and on some regulatory mechanisms that ensure the functioning of this class of molecules. We also outline some examples of micro-RNAs use as diagnostic and therapeutic targets.
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Aterosclerosis , Humanos , MicroARNsRESUMEN
MicroRNAs are small noncoding single-stranded RNAs that regulate gene expression. Today, we see an increasing number of studies highlighting the important role of microRNAs in the development and progression of cardiovascular diseases caused by atherosclerotic lesions of arteries. We review the available scientific data on association of the expression of these biomolecules with instability of atherosclerotic plaques in animal models and humans. We made special emphasis on miR-21, -100, -127, -133, -143/145, -221/222, and -494 because they were analyzed in more than one study. We discuss the possibility of microRNAs using in the diagnosis and therapy of atherosclerosis and its complications.
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MicroARNs/fisiología , Placa Aterosclerótica/patología , Animales , Biomarcadores , Humanos , Placa Aterosclerótica/genéticaRESUMEN
In this study, we for the first time described the variability of methylation levels of 71 CpG sites in microRNA genes in leukocytes and blood vessels (coronary artery atherosclerotic plaques, intact internal thoracic arteries, and great saphenous veins) in patients with atherosclerosis using the Infinium HumanMethylation27 BeadChip microarray. Most of the analyzed CpG sites were characterized by the low variability, and most of these low-variable sites were hypomethylated in all tissue samples. CpG sites in coronary artery atherosclerotic plaques and leukocytes were similar in their methylation status. The highest variability of CpG methylation levels between different tissues was found for the CpG sites of the MIR10B gene; the methylation levels of these sites in leukocytes and atherosclerotic arteries were lower than in intact blood vessels. We also found that several cardiovascular disease risk factors, as well as medications, might affect methylation levels of CpG sites in microRNAs.
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Enfermedad de la Arteria Coronaria/metabolismo , Vasos Coronarios/metabolismo , Islas de CpG , Metilación de ADN , Arterias Mamarias/metabolismo , MicroARNs/metabolismo , Placa Aterosclerótica/metabolismo , Vena Safena/metabolismo , Enfermedad de la Arteria Coronaria/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Placa Aterosclerótica/genéticaRESUMEN
This review provides modern data on the spectrum and the functional significance of micro-RNAs involved in atherogenesis and on some regulatory mechanisms that ensure the functioning of this class of molecules. We also outline some examples of micro-RNAs use as diagnostic and therapeutic targets.
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Aterosclerosis , Humanos , MicroARNs , Músculo Liso VascularRESUMEN
For identification of somatic mitochondrial DNA (mtDNA) mutations, the mtDNA major noncoding region (D-loop) sequence in blood samples and carotid atherosclerosis plaques from patients with atherosclerosis was analyzed. Five point heteroplasmic positions were observed in 4 of 23 individuals (17%). Only in two cases could heteroplasmy have resulted from somatic mutation, whereas three heteroplasmic positions were found in both vascular tissue and blood. In addition, length heteroplasmy in a polycytosine stretches was registered at nucleotide positions 303-315 in 16 individuals, and also in the 16184-16193 region--in four patients. The results suggest that somatic mtDNA mutations can occur during atherosclerosis, but some heteroplasmic mutations may appear in all tissues, possibly being inherited.
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Aterosclerosis/genética , Arterias Carótidas/patología , ADN Mitocondrial/genética , Placa Aterosclerótica/genética , Anciano , ADN Mitocondrial/sangre , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Placa Aterosclerótica/sangre , Placa Aterosclerótica/patología , Mutación Puntual/genética , Polimorfismo de Nucleótido SimpleRESUMEN
The first data on the existence of multiple genomic rearrangements, such as copy number variation (CNV) and copy neutral loss of heterozygosity, in vascular tissues and peripheral blood leukocytes from patients with atherosclerosis, are presented. Compared to internal mammary arteries and peripheral blood leukocytes, right coronary arteries in the atherosclerotic plaque area presented with a higher CNV length and number of genes located in their vicinity. In each of the patients, 6-16% of CNVs were common to the three types of tissues examined. Therefore, most of the copy number variations in the tissues affected by atherosclerosis (from 68 to 91% in each of the patients) were of somatic origin. The gains in 3p21.31 (CACNA2D2), 7q32.1 (FLNC), 19p13.3 (C19orf29, PIP5K1C), and 21q22.3 (COL6A1) were detected in vascular tissues but not in peripheral blood leukocytes. Moreover, the gain in 7p15.2 (SKAP2), detected in the patients with atherosclerosis, did not overlap with any CNV regions currently reported in The Database of Genomic Variants. The loss of heterozygosity in 12 out of 13 chromosomal regions was copy neutral and covered tumor suppressor genes (SFRP1, CEBPD, RB1CC1, DIRAS3, TUSC3, and ZDHHC2).
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Aterosclerosis/genética , Cromosomas Humanos/genética , Variación Genética , Leucocitos , Arterias Mamarias , Anciano , Bases de Datos Genéticas , Dosificación de Gen , Humanos , Masculino , Persona de Mediana EdadRESUMEN
To date the question of epigenetic mechanisms of gene regulation in the context of cardiovascular diseases is of a considerable interest. Here, for the first time DNA methylation profiles of vascular tissues of atherosclerotic patients have been analyzed with using the microarray Infinium HumanMethylation27 BeadChip ("Illumina", USA). As the result, within 286 genes 314 CpG-sites that varied significantly in the DNA methylation level between the tissue samples of carotid (in the area of atherosclerotic plaques and nearby macroscopically intact tissues of the vascular wall) and mammary arteries as well saphenous veins have been identified. The most pronounced differences in the methylation level were registered for CpG-sites of homeobox genes HOXA2 and HOXD4 as well as imprinted gene MEST. In particular, these genes were found to be hypomethylated in the carotid atherosclerotic plaques compared to their methylation patterns in intact tissues of internal mammary arteries and saphenous veins.