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1.
Medicine (Baltimore) ; 98(39): e17298, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574854

RESUMO

Recently, studies have shown significant association between the rs2000999 polymorphism in the haptoglobin-encoding gene (HP) and low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, which are important risk factors for cardiovascular diseases. However, the association of rs2000999 with serum lipids in Latin American diabetic populations is still uncharacterized. Here, we analyzed the association of rs2000999 with TC, high-density lipoprotein cholesterol (HDL-C), and LDL-C levels in 546 Mexican adults with type 2 diabetes (T2D) and in 654 controls without T2D. In this observational case-control study we included adults from 4 centers of the Mexican Social Security Institute in Mexico City recruited from 2012 to 2015. TC, HDL-C, LDL-C, triglycerides (TG), and glucose levels were measured by an enzymatic colorimetric method. The variant rs2000999 was genotyped using TaqMan real time polymerase chain reaction. The percentage of Native-American ancestry showed a negative association with the rs2000999 A allele. In contrast, the rs2000999 A allele had a strong positive association with European ancestry, and to a lesser extent, with African ancestry. Linear regression was used to estimate the association between the variant rs2000999 and lipid concentrations, using different genetic models. Under codominant and recessive models, rs2000999 was significantly associated with TC and LDL-C levels in the T2D group and in controls without T2D. In addition, the group with T2D showed a significant association between the variant and HDL-C levels. In summary, the rs2000999 A allele in Mexican population is positively associated with the percentage of European and negatively associated with Native American ancestry. Carriers of the A allele have increased levels of TC and LDL-C, independently of T2D diagnosis, and also increased concentrations of HDL-C in the T2D sample.


Assuntos
Doenças Cardiovasculares , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colesterol/sangue , Diabetes Mellitus Tipo 2 , Haptoglobinas , Adulto , Biomarcadores/análise , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Haptoglobinas/análise , Haptoglobinas/genética , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
2.
Nihon Yakurigaku Zasshi ; 154(2): 56-60, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31406043

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand activated transcription factor known to regulate fatty acid metabolism. Thiazolidinediones (TZDs), PPARγ synthetic agonists, currently used to treat patients with type 2 diabetes, have been shown to lower the blood pressure and protect against vascular diseases such as atherosclerosis. In line with these findings, it has been reported that individuals with loss-of-function mutations of PPARγ developed sever early-onset hypertension in addition to metabolic abnormalities. Accumulating evidences suggest PPARγ in the vasculature has protective effects on cardiovascular disease despite unclear mechanism. Because of ubiquitous expression of PPARγ, TZDs are well-known to be associated with serious side effects such as weight gain, fluid retention, and bone fractures. Thus identification of mechanisms on tissue-specific PPARγ activity may lead to the development of targeted treatment which is characterized by no deleterious effects. This review discusses role of PPARγ in cardiovascular disease.


Assuntos
Doenças Cardiovasculares/genética , PPAR gama/genética , Tiazolidinedionas/farmacologia , Fatores de Transcrição/genética , Pressão Sanguínea , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , PPAR gama/agonistas
3.
Adv Exp Med Biol ; 1193: 53-67, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368097

RESUMO

Aldehyde dehydrogenase 2 (ALDH2) is a non-cytochrome P450 mitochondrial aldehyde oxidizing enzyme. It is best known for its role in the metabolism of acetaldehyde, a common metabolite from alcohol drinking. More evidences have been accumulated in recent years to indicate a greater role of ALDH2 in the metabolism of other endogenous and exogenous aldehydes, especially lipid peroxidation-derived reactive aldehyde under oxidative stress. Many cardiovascular diseases are associated with oxidative stress and mitochondria dysfunction. Considering that an estimated 560 million East Asians carry a common ALDH2 deficient variant which causes the well-known alcohol flushing syndrome due to acetaldehyde accumulation, the importance of understanding the role of ALDH2 in these diseases should be highlighted. There are several unfavorable cardiovascular conditions that are associated with ALDH2 deficiency. This chapter reviews the function of ALDH2 in various pathological conditions of the heart in relation to aldehyde toxicity. It also highlights the importance and clinical implications of interaction between ALDH2 deficiency and alcohol drinking on cardiovascular disease among the East Asians.


Assuntos
Acetaldeído/efeitos adversos , Consumo de Bebidas Alcoólicas , Aldeído-Desidrogenase Mitocondrial/genética , Doenças Cardiovasculares/genética , Grupo com Ancestrais do Continente Asiático , Humanos
4.
High Blood Press Cardiovasc Prev ; 26(4): 321-329, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31325087

RESUMO

Cardiovascular disease (CVD) remains the leading cause of morbility and mortality worldwide. The identification of common cardiovascular risk factors has led to the development of effective treatments that enabled a significant reduction of the global cardiovascular disease burden. However, a significant proportion of cardiovascular risk remains unexplained by these risk factors leaving many individuals at risk of cardiovascular events despite good control of the risk factors. Recent randomized clinical trials and Mendelian randomization studies have suggested that inflammation explains a significant proportion of the residual cardiovascular risk in subjects with good control of risk factors. An accelerated process of vascular ageing is increasingly recognized as a potential mechanism by which inflammation might increase the risk of CVD. In turn, cellular ageing represents an important source of inflammation within the vascular wall, potentially creating a vicious cycle that might promote progression of atherosclerosis, independently from the individual cardiovascular risk factor burden. In this review, we summarise current evidence suggesting a role for biological ageing in CVD and how inflammation might act as a key mediator of this association.


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Telômero/metabolismo , Fatores Etários , Envelhecimento/genética , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Senescência Celular , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Medição de Risco , Fatores de Risco , Transdução de Sinais , Telômero/genética , Telômero/patologia , Homeostase do Telômero , Encurtamento do Telômero , Fatores de Tempo
5.
Methodist Debakey Cardiovasc J ; 15(1): 62-69, 2019 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31049151

RESUMO

Cardiovascular disease is the leading cause of death worldwide, and elevated lipid levels is a major contributor. Gene delivery, which involves controlled transfer of nucleic acids into cells and tissues, has been widely used in research to study lipid metabolism and physiology. Several technologies have been developed to somatically overexpress, silence, or disrupt genes in animal models and have greatly advanced our knowledge of metabolism. This is particularly true with regard to the liver, which plays a central role in lipoprotein metabolism and is amenable to many delivery approaches. In addition to basic science applications, many of these delivery technologies have potential as gene therapies for both common and rare lipid disorders. This review discusses three major gene delivery technologies used in lipid research-including adeno-associated viral vector overexpression, antisense oligonucleotides and small interfering RNAs, and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome editing system-and examines their potential therapeutic applications.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Dislipidemias/terapia , Terapia Genética/métodos , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Animais , Sistemas CRISPR-Cas , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Dependovirus/genética , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/genética , Edição de Genes/métodos , Terapia Genética/efeitos adversos , Vetores Genéticos , Humanos , Oligonucleotídeos Antissenso/genética , RNA Interferente Pequeno/genética , Terapêutica com RNAi/métodos , Resultado do Tratamento
6.
Cell Mol Life Sci ; 76(18): 3497-3514, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31089747

RESUMO

Accurate determination of microRNA expression levels is a prerequisite in using these small non-coding RNA molecules as novel biomarkers in disease diagnosis and prognosis. Quantitative PCR is the method of choice for measuring the expression levels of microRNAs. However, a major obstacle that affects the reliability of results is the lack of validated reference controls for data normalization. Various non-coding RNAs have previously been used as reference controls, but their use may lead to variations and lack of comparability of microRNA data among the studies. Despite the growing number of studies investigating microRNA profiles to discriminate between healthy and disease stages, robust reference controls for data normalization have so far not been established. In the present article, we provide an overview of different reference controls used in various diseases, and highlight the urgent need for the identification of suitable reference controls to produce reliable data. Our analysis shows, among others, that RNU6 is not an ideal normalizer in studies using patient material from different diseases. Finally, our article tries to disclose the challenges to find a reference control which is uniformly and stably expressed across all body tissues, fluids, and diseases.


Assuntos
MicroRNAs/metabolismo , Biomarcadores/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/patologia , Hepatite B/genética , Hepatite B/patologia , Humanos , MicroRNAs/sangue , Neoplasias/genética , Neoplasias/patologia , Prognóstico , RNA Nuclear Pequeno/sangue , RNA Nuclear Pequeno/metabolismo , Tuberculose/genética , Tuberculose/patologia
7.
Maturitas ; 124: 68-71, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31097182

RESUMO

There is an ongoing misperception that women under 60 years of age are at low risk of cardiovascular disease (CVD). As there is an important variation in risk among women in this age group, we need to tailor risk assessment by using additional risk parameters during their life-course. For this, valuable tools are family risk, female-specific risk factors and inflammatory co-morbidities, which can be enriched by measuring the coronary artery calcium (CAC) score using computerized tomography. Depending on the results, we can readily adapt lifestyle advice and preventive treatment to every individual woman. Progress has been made in the recognition of stable and unstable manifestations of ischemic heart disease in middle-aged women. Whereas the traditional cardiovascular risk factors are involved in classic obstructive coronary disease, female-specific risk variables, inflammatory co-morbidities and psychosocial stress are also involved in other types of ischemic disease. We therefore need a more sex- and gender-sensitive way to look at women's cardiovascular health.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Inflamação/epidemiologia , Doenças Cardiovasculares/genética , Comorbidade , Feminino , Humanos , Estilo de Vida , Medição de Risco , Fatores de Risco , Fatores Sexuais , Estresse Psicológico/epidemiologia , Saúde da Mulher
8.
Ter Arkh ; 91(1): 71-77, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-31090375

RESUMO

AIM: To evaluate the association of a complex of cardiovascular risk factors and genetic markers with the development of high albuminuria among patients with arterial hypertension in the population of Mountain Shoriya, taking into account ethnicity. MATERIALS AND METHODS: A clinical epidemiological study of a compactly residing population in remote areas of Mountain Shoria was carried out. 1409 people were examined [901 people - representatives of the indigenous nationality (Shorians), 508 people - representatives of non-indigenous nationality (90% of them are Caucasians)]. Hypertension was diagnosed according to the National Guidelines of the Russian Society of Cardiology/the Russian Medical Society on Arterial Hypertension (2010). All patients underwent clinical, laboratory and instrumental investigation. To study the state of the kidneys, the concentration (the presence of elevated levels) of albumin (albuminuria) in the morning portion of urine by an immunoturbidimetric method was analyzed. Polymorphisms of genes ACE (I/D, rs4340), АGT (c.803T>C, rs699), AGTR1 (А1166С, rs5186), ADRB1 (с.145A>G, Ser49Gly, rs1801252), ADRA2B (I/D, rs28365031), MTHFR (c.677С>Т, Ala222Val, rs1801133) and NOS3 (VNTR, 4b/4a) were tested using PCR. RESULTS: In the group of shors with arterial hypertension, high albuminuria was associated with polymorphisms of the ACE genes (OR=2.05), ADRA2B (OR=6.00), elevated triglyceride level (OR=2.86), decreased index of cholesterol of high density lipoproteins (OR=5.57) and increased index of low density lipoproteins (OR=2.49); in the new population - with polymorphisms of the AGTR1 genes (OR=8.66), ADRA2B (OR=6.53), MTHFR (OR=7.16), obesity (OR=2.72), and abdominal obesity (OR=3.14). CONCLUSION: The primary predictors determining the development of high albuminuria among patients with arterial hypertension in both ethnic groups were genetic ones. In addition to them, non-genetic risk factors also contributed to the development of this organ damage to the kidneys: age and lipid metabolism disorders in representatives of indigenous nationality; age and abdominal obesity in the examined patients non-indigenous nationality.


Assuntos
Albuminas/metabolismo , Albuminúria/etnologia , Doenças Cardiovasculares/genética , Grupos Étnicos/genética , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Receptores Adrenérgicos alfa 2/genética , Albuminúria/genética , Doenças Cardiovasculares/etnologia , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hipertensão/etnologia , Lipoproteínas HDL/metabolismo , Obesidade Abdominal/etnologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Fatores de Risco , Federação Russa/epidemiologia , Triglicerídeos/metabolismo
9.
Arch Endocrinol Metab ; 63(3): 215-221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31066762

RESUMO

OBJECTIVE: This study investigated the familial aggregation and heritability of markers of metabolic risk, physical activity, and physical fitness in nuclear families from Muzambinho (Minas Gerais, Brazil). SUBJECTS AND METHODS: The study included members of 139 families, comprising 97 fathers (aged 40 ± 7 years), 129 mothers (35 ± 6 years), 136 sons (12 ± 4 years), and 121 daughters (12 ± 5 years). Evaluated markers included (A) body mass index, waist circumference, glycemia, and cholesterolemia, as metabolic risk markers; (B) total weekly volume of physical activity, as a physical activity marker; and (C) relative muscle strength, as a physical fitness marker. Correlations between family members and heritability (h2) were estimated using the software S.A.G.E. RESULTS: Significant familial correlations were obtained between parents-offspring for glycemia and cholesterolemia (both ρ = 0.21, p < 0.05) and relative muscle strength (ρ = 0.23, p < 0.05), and between siblings for waist circumference, glycemia, total weekly volume of physical activity, and relative muscle strength (ρ variation 0.25 to 0.36, p < 0.05). Heritability values were significant for almost all variables (h2 variations: 20% to 57% for metabolic risk markers, 22% for the total weekly volume of physical activity, and 50% for relative muscle strength), except for waist circumference (h2 = 15%, p = 0.059). CONCLUSION: The presence of significant correlations between family members and/or significant heritability strengthens the possible genetic and/or common familial environment influence on metabolic risk markers, total weekly volume of physical activity, and relative muscle strength.


Assuntos
Exercício , Síndrome Metabólica/genética , Adolescente , Adulto , Biomarcadores , Composição Corporal , Índice de Massa Corporal , Brasil/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Criança , Exercício/fisiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Força Muscular/fisiologia , Núcleo Familiar , Aptidão Física/fisiologia , Fatores de Risco , Circunferência da Cintura , Adulto Jovem
10.
Life Sci ; 233: 116440, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047893

RESUMO

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Non-coding RNAs including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs) have been reported to participate in pathological developments of CVDs through various mechanisms. Among them, the networks among lncRNAs/circRNAs, miRNAs, and mRNAs have recently attracted attention. Understanding the molecular mechanism could aid the discovery of therapeutic targets or strategies in CVDs including atherosclerosis, myocardial infarction (MI), hypertrophy, heart failure (HF) and cardiomyopathy. In this review, we summarize the latest research involving the lncRNA/circRNA-miRNA-mRNA axis in CVDs, with emphasis on the molecular mechanism.


Assuntos
Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Redes Reguladoras de Genes , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA/genética , Animais , Humanos , Transdução de Sinais
11.
Lancet ; 393(10183): 1831-1842, 2019 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-30955975

RESUMO

BACKGROUND: Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom drink). METHODS: The prospective China Kadoorie Biobank enrolled 512 715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161 498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self-reported drinking patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology-ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake. FINDINGS: 33% (69 897/210 205) of men reported drinking alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302 510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14 930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers. In contrast, although genotype-predicted mean male alcohol intake varied widely (from 4 to 256 g per week-ie, near zero to about four drinks per day), it did not have any U-shaped associations with risk. For stroke, genotype-predicted mean alcohol intake had a continuously positive log-linear association with risk, which was stronger for intracerebral haemorrhage (relative risk [RR] per 280 g per week 1·58, 95% CI 1·36-1·84, p<0·0001) than for ischaemic stroke (1·27, 1·13-1·43, p=0·0001). For myocardial infarction, however, genotype-predicted mean alcohol intake was not significantly associated with risk (RR per 280 g per week 0·96, 95% CI 0·78-1·18, p=0·69). Usual alcohol intake in current drinkers and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few drank and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction. INTERPRETATION: Genetic epidemiology shows that the apparently protective effects of moderate alcohol intake against stroke are largely non-causal. Alcohol consumption uniformly increases blood pressure and stroke risk, and appears in this one study to have little net effect on the risk of myocardial infarction. FUNDING: Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust.


Assuntos
Álcool Desidrogenase/metabolismo , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Doenças Cardiovasculares/genética , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Aldeído-Desidrogenase Mitocondrial/metabolismo , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Hemorragia Cerebral/epidemiologia , China/epidemiologia , Extremo Oriente/epidemiologia , Feminino , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia
12.
Nat Commun ; 10(1): 1891, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015401

RESUMO

Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and can be used to quantify future risk of medication taking. Here, we conduct GWASs of self-reported medication use from 23 medication categories in approximately 320,000 individuals from the UK Biobank. A total of 505 independent genetic loci that meet stringent criteria (P < 10-8/23) for statistical significance are identified. We investigate the implications of these GWAS findings in relation to biological mechanism, potential drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes are 16 known therapeutic-effect target genes for medications from 9 categories. Two of the medication classes studied are for disorders that have not previously been subject to large GWAS (hypothyroidism and gastro-oesophageal reflux disease).


Assuntos
Uso de Medicamentos/estatística & dados numéricos , Genoma Humano , Estudo de Associação Genômica Ampla , Testes Farmacogenômicos/estatística & dados numéricos , Medicamentos sob Prescrição/uso terapêutico , Idoso , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Bases de Dados Factuais , Feminino , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/genética , Gastroenteropatias/fisiopatologia , Loci Gênicos , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/tratamento farmacológico , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/fisiopatologia , Autoadministração , Autorrelato , Reino Unido
13.
Biol Pharm Bull ; 42(4): 531-537, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930412

RESUMO

DNA suffers various types of damage even in a normal condition, although they are rapidly repaired by mechanisms called DNA repair. Most progeroid syndromes are caused by genetic defects in specific molecules involved in the DNA repair. DNA damage activates a broad range of signaling pathway that leads to repair, cell cycle arrest, apoptosis and so on, which is called DNA damage response. Recent studies revealed that persistent DNA damage response triggers induction of cell senescence and senescence-associated secretory phenotype (SASP). Here, we review recent advances in the understanding of the molecular mechanisms by which SASP components are regulated, and discuss the possible roles of DNA damage and the DNA damage response, and SASP in the pathogenesis of cardiovascular disease.


Assuntos
Doenças Cardiovasculares , Senescência Celular , Dano ao DNA , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Instabilidade Genômica , Humanos , Inflamação/genética , Inflamação/patologia
14.
Nat Methods ; 16(5): 381-386, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962620

RESUMO

Single-cell transcriptomics provides an opportunity to characterize cell-type-specific transcriptional networks, intercellular signaling pathways and cellular diversity with unprecedented resolution by profiling thousands of cells in a single experiment. However, owing to the unique statistical properties of scRNA-seq data, the optimal measures of association for identifying gene-gene and cell-cell relationships from single-cell transcriptomics remain unclear. Here, we conducted a large-scale evaluation of 17 measures of association for their ability to reconstruct cellular networks, cluster cells of the same type and link cell-type-specific transcriptional programs to disease. Measures of proportionality were consistently among the best-performing methods across datasets and tasks. Our analysis provides data-driven guidance for gene and cell network analysis in single-cell transcriptomics.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/genética , Análise de Célula Única/métodos , Animais , Doenças Cardiovasculares/genética , Linhagem Celular , Doenças do Sistema Nervoso Central/genética , Análise por Conglomerados , Humanos , Camundongos , Reprodutibilidade dos Testes , Análise de Sequência de RNA/métodos , Software
15.
Hum Genet ; 138(6): 625-634, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30963242

RESUMO

Rare heterozygous variants in SMAD6 have been identified as a significant genetic contributor to bicuspid aortic valve-associated thoracic aortic aneurysm on one hand and non-syndromic midline craniosynostosis on the other. In this study, we report two individuals with biallelic missense variants in SMAD6 and a complex cardiac phenotype. Trio exome sequencing in Proband 1, a male who had aortic isthmus stenosis, revealed the homozygous SMAD6 variant p.(Ile466Thr). He also had mild intellectual disability and radio-ulnar synostosis. Proband 2 is a female who presented with a more severe cardiac phenotype with a dysplastic and stenotic pulmonary valve and dilated cardiomyopathy. In addition, she had vascular anomalies, including a stenotic left main coronary artery requiring a bypass procedure, narrowing of the proximal left pulmonary artery and a venous anomaly in the brain. Proband 2 has compound heterozygous SMAD6 missense variants, p.(Phe357Ile) and p.(Ser483Pro). Absence of these SMAD6 variants in the general population and high pathogenicity prediction scores suggest that these variants caused the probands' phenotypes. This is further corroborated by cardiovascular anomalies and appendicular skeletal defects in Smad6-deficient mice. SMAD6 acts as an inhibitory SMAD and preferentially inhibits bone morphogenetic protein (BMP)-induced signaling. Our data suggest that biallelic variants in SMAD6 may affect the inhibitory activity of SMAD6 and cause enhanced BMP signaling underlying the cardiovascular anomalies and possibly other clinical features in the two probands.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Proteína Smad6/genética , Alelos , Animais , Doenças Cardiovasculares/patologia , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Camundongos , Fenótipo , Sequenciamento Completo do Exoma/métodos
16.
Hum Genet ; 138(6): 547-561, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968250

RESUMO

Air pollution is recognized as causal factor for cardiovascular disease (CVD) and is associated with multiple CVD risk factors. Substantial research effort has been invested in understanding the linkages between genetic variation and CVD risk, resulting in over 50 CVD-associated genetic loci. More recently, gene-air pollution interaction studies have quantified the contribution of genetic variation to inter-individual heterogeneity in air pollution health risks, and aided in elucidating mechanisms of air pollution exposure health risks. Here, we perform a comprehensive review of gene-air pollution interaction studies for CVD, as well as risk factors and emerging CVD biomarkers. The literature review revealed that most published interaction studies have been candidate gene studies, causing observed interactions to cluster in a few genes related to detoxification (GSTM1 and GSTT1), inflammation (IL-6), iron processing (HFE), and microRNA processing (GEMIN4 and DGCR8). There have been a few genome-wide interaction studies with results indicating that interactions extend beyond commonly considered genetic loci. Gene-air pollution interactions are observed for exposure periods ranging from hours to years and a variety of air pollutants including particulate matter, gaseous pollutants, and pollutant sources such as traffic. Though the existing evidence for the existence of relevant gene-air pollution interactions for CVD outcomes is substantial, it could be strengthened by improved replication and meta-analyses as well as functional validation.


Assuntos
Poluição do Ar , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Exposição Ambiental/efeitos adversos , Interação Gene-Ambiente , Saúde Ambiental/métodos , Predisposição Genética para Doença/etiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Medição de Risco/métodos , Fatores de Risco
17.
Respir Res ; 20(1): 64, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940143

RESUMO

BACKGROUND: A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. METHODS: We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. RESULTS: RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008). CONCLUSION: In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.


Assuntos
Doenças Cardiovasculares/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Bases de Dados Genéticas/tendências , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Característica Quantitativa Herdável
19.
Vascul Pharmacol ; 114: 23-30, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30910128

RESUMO

In recent years, it has been revealed that majority of the genome is transcribed in a cell- and context-specific manner into a vast array of RNA transcripts that do not encode proteins. Increasing evidence suggests that non-coding RNAs, especially long non-coding RNAs (lncRNAs) are essential regulators of gene expression and other cellular processes, including in the cardiovascular context. In this review, we discuss lncRNAs and their function during endothelial and vascular smooth cell differentiation, function and homeostasis as well as their role in vessel wall injury response and vascular disease pathophysiology. Although our understanding of lncRNAs is still emerging, these examples reveal important insights on how lncRNAs may ultimately be used in clinic as therapeutic targets for cardiovascular disease.


Assuntos
Vasos Sanguíneos/metabolismo , Doenças Cardiovasculares/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Vasos Sanguíneos/patologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Diferenciação Celular , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neovascularização Fisiológica , RNA Longo não Codificante/genética , Transdução de Sinais , Remodelação Vascular
20.
Subcell Biochem ; 91: 1-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30888647

RESUMO

The prevalence of age-associated disease is increasing at a striking rate globally and there is evidence to suggest that the ageing process may actually begin before birth. It has been well-established that the status of both the maternal and early postnatal environments into which an individual is exposed can have huge implications for the risk of developing age-associated disease, including cardiovascular disease (CVD), type-2 diabetes (T2D) and obesity in later life. Therefore, the dissection of underlying molecular mechanisms to explain this phenomenon, known as 'developmental programming' is a highly investigated area of research. This book chapter will examine the epidemiological evidence and the animal models of suboptimal maternal and early postnatal environments and will discuss the progress being made in the development of safe and effective intervention strategies which ultimately could target those 'programmed' individuals who are known to be at-risk of age-associated disease.


Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Obesidade/etiologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Envelhecimento/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/prevenção & controle , Epigênese Genética , Feminino , Humanos , Modelos Animais , Obesidade/genética , Obesidade/prevenção & controle , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
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