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1.
J Transl Med ; 18(1): 408, 2020 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129318

RESUMO

COronaVIrus Disease 19 (COVID-19) is caused by the infection of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are respiratory, many patients also display acute myocardial injury and chronic damage to the cardiovascular system. Understanding both direct and indirect damage caused to the heart and the vascular system by SARS-CoV-2 infection is necessary to identify optimal clinical care strategies. The homeostasis of the cardiovascular system requires a tight regulation of the gene expression, which is controlled by multiple types of RNA molecules, including RNA encoding proteins (messenger RNAs) (mRNAs) and those lacking protein-coding potential, the noncoding-RNAs. In the last few years, dysregulation of noncoding-RNAs has emerged as a crucial component in the pathophysiology of virtually all cardiovascular diseases. Here we will discuss the potential role of noncoding RNAs in COVID-19 disease mechanisms and their possible use as biomarkers of clinical use.


Assuntos
Doenças Cardiovasculares/complicações , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , RNA não Traduzido , Animais , Arritmias Cardíacas/complicações , Betacoronavirus , Cardiomegalia/complicações , Doenças Cardiovasculares/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Homeostase , Humanos , Inflamação/complicações , Camundongos , Pandemias , Peptidil Dipeptidase A/genética , Sistema Renina-Angiotensina , Transcriptoma
2.
Nat Commun ; 11(1): 5404, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106479

RESUMO

There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.


Assuntos
Peso ao Nascer , Doenças Cardiovasculares/genética , Herança Materna , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Análise da Randomização Mendeliana , Noruega/epidemiologia , Herança Paterna , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
3.
PLoS One ; 15(9): e0238304, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915819

RESUMO

Epistasis analysis elucidates the effects of gene-gene interactions (G×G) between multiple loci for complex traits. However, the large computational demands and the high multiple testing burden impede their discoveries. Here, we illustrate the utilization of two methods, main effect filtering based on individual GWAS results and biological knowledge-based modeling through Biofilter software, to reduce the number of interactions tested among single nucleotide polymorphisms (SNPs) for 15 cardiac-related traits and 14 fatty acids. We performed interaction analyses using the two filtering methods, adjusting for age, sex, body mass index (BMI), waist-hip ratio, and the first three principal components from genetic data, among 2,824 samples from the Ludwigshafen Risk and Cardiovascular (LURIC) Health Study. Using Biofilter, one interaction nearly met Bonferroni significance: an interaction between rs7735781 in XRCC4 and rs10804247 in XRCC5 was identified for venous thrombosis with a Bonferroni-adjusted likelihood ratio test (LRT) p: 0.0627. A total of 57 interactions were identified from main effect filtering for the cardiac traits G×G (10) and fatty acids G×G (47) at Bonferroni-adjusted LRT p < 0.05. For cardiac traits, the top interaction involved SNPs rs1383819 in SNTG1 and rs1493939 (138kb from 5' of SAMD12) with Bonferroni-adjusted LRT p: 0.0228 which was significantly associated with history of arterial hypertension. For fatty acids, the top interaction between rs4839193 in KCND3 and rs10829717 in LOC107984002 with Bonferroni-adjusted LRT p: 2.28×10-5 was associated with 9-trans 12-trans octadecanoic acid, an omega-6 trans fatty acid. The model inflation factor for the interactions under different filtering methods was evaluated from the standard median and the linear regression approach. Here, we applied filtering approaches to identify numerous genetic interactions related to cardiac-related outcomes as potential targets for therapy. The approaches described offer ways to detect epistasis in the complex traits and to improve precision medicine capability.


Assuntos
Doenças Cardiovasculares/epidemiologia , Biologia Computacional/métodos , Epistasia Genética , Ácidos Graxos/sangue , Marcadores Genéticos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Adulto Jovem
4.
Nat Commun ; 11(1): 4592, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929089

RESUMO

Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35-50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.


Assuntos
Doenças Cardiovasculares/complicações , Estado Pré-Diabético/complicações , Glicemia/metabolismo , Doenças Cardiovasculares/genética , Intervalos de Confiança , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Jejum/sangue , Humanos , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Razão de Chances , Estado Pré-Diabético/sangue , Estado Pré-Diabético/genética , Insuficiência Renal Crônica/complicações , Fatores de Risco , Acidente Vascular Cerebral/complicações
5.
BMC Med Genet ; 21(1): 179, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917134

RESUMO

BACKGROUND: Cardiovascular diseases are still the major cause of death in the Western world, with different outcomes between the two genders. Efforts to identify those at risk are therefore given priority in the handling of health resources. Thrombospondins (TSP) are extracellular matrix proteins associated with cardiovascular diseases. The aim of this study was to investigate variations in single nucleotide polymorphisms (SNPs) of TSP-1 and plasma expression, and associations with mortality from a gender perspective. METHODS: A population of 470 community-living persons were invited to participate. The participants were followed for 7.9 years and underwent a clinical examination and blood sampling. SNP analyses of TSP-1 rs1478604 and rs2228262 using allelic discrimination and plasma measurement of TSP-1 using ELISA were performed, RESULTS: During the follow-up period, 135 (28.7%) all-cause and 83 (17.7%) cardiovascular deaths were registered. In the female population, the A/A genotype of rs2228262 and the T/T genotype of rs1478604 exhibited significantly more cardiovascular deaths compared with the A/G and G/G, or the T/C and C/C genotypes amalgamated (rs2228262: 13.7% vs 2.0%; Χ2:5.29; P = 0.02; rs1478604:17.7% vs 4.7%; Χ2:9.50; P = 0.002). Applied in a risk evaluation, the A/A, or T/T genotypes exhibited an increased risk of cardiovascular mortality (rs2228262: HR: 7.1; 95%CI 1.11-45.8; P = 0.04; rs1478604: HR: 3.18; 95%CI 1.35-7.50; p = 0.008). No differences among the three genotypes could be seen in the male group. CONCLUSION: In this study the female group having the A/A genotype of rs2228262, or the T/T genotype of rs1478604 of TSP-1 exhibited higher cardiovascular mortality after a follow-up of almost 8 years. No corresponding genotype differences could be found in the male group. Genotype evaluations should be considered as one of the options to identify individuals at risk. However, this study should be regarded as hypothesis-generating, and more research in the field is needed.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Trombospondina 1/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Feminino , Frequência do Gene , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida
6.
DNA Cell Biol ; 39(11): 2085-2094, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32955941

RESUMO

Basic and clinical research have demonstrated that osteoprotegerin (OPG) plays an important role in the development and progression of cardiovascular diseases. The aim of this study was to evaluate the association of four polymorphic sites (rs2073618, rs3134069, rs3134070, and rs3102735) of OPG gene with premature coronary artery disease (pCAD), and with cardiometabolic parameters. The polymorphisms were genotyped using 5' exonuclease TaqMan genotyping assays with real-time PCR in 1098 individuals with pCAD and 1041 healthy controls. rs2073618 polymorphism was associated with a high risk of developing pCAD according to different inheritance models: additive (p = 0.001; odds ratio [OR] = 1.283), dominant (p = 0.006; OR = 1.383), recessive (p = 0.011; OR = 1.423), and codominant 2 (p = 0.001; OR = 1.646). The four polymorphisms were associated with different cardiovascular risk factors in individuals with pCAD and controls. Our results suggest that OPG rs2073618 polymorphism is associated with an increased risk of pCAD. In addition, two haplotypes were associated with pCAD, one increasing the risk (CACT) and another one as protective (GACC).


Assuntos
Doença da Artéria Coronariana/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Osteoprotegerina/genética , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Feminino , Variação Genética/genética , Genótipo , Haplótipos , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
7.
Nat Commun ; 11(1): 3861, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737316

RESUMO

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.


Assuntos
Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Análise da Randomização Mendeliana/estatística & dados numéricos , Modelos Genéticos , Transcriptoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Simulação por Computador , Bases de Dados Factuais , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Funções Verossimilhança , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Herança Multifatorial , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
8.
Cardiovasc Ther ; 2020: 9397109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821285

RESUMO

Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown in vitro also counters cytokine-mediated induction of the CRP gene. Mechanistically, apabetalone reduces the cytokine-driven increase in BRD4 BET occupancy at the CRP promoter, confirming that transcription of CRP is BET-dependent. In patients with stable coronary disease, plasma APR proteins CRP, IL-1 receptor antagonist, and fibrinogen γ decrease after apabetalone treatment versus placebo, resulting in a predicted downregulation of the APR pathway and cytokine targets. We conclude that CRP and components of the APR pathway are regulated by BET proteins and that apabetalone counters chronic cytokine signaling in patients.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Quinazolinonas/farmacologia , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Proteína C-Reativa/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Endotoxemia/genética , Endotoxemia/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas , Componente Amiloide P Sérico/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , alfa-Macroglobulinas/genética , alfa-Macroglobulinas/metabolismo
9.
High Blood Press Cardiovasc Prev ; 27(5): 363-371, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740853

RESUMO

Epigenetic processing takes centre stage in cardiometabolic diseases (obesity, metabolic syndrome, type 2 diabetes, hypertension), where it participates in adiposity, inflammation, endothelial dysfunction, vascular insulin resistance and atherosclerosis. Epigenetic modifications, defined as heritable changes in gene expression that do not entail mutation in the DNA sequence, are mainly induced by environmental stimuli (stress, pollution, cigarette smoking) and are gaining considerable interest due to their causal role in cardiovascular disease, and their amenability to pharmacological intervention. Importantly, epigenetic modifications acquired during life can be transmitted to the offspring and exert their biological effects across multiple generations. Indeed, such transgenerational transmission of epigenetic signals may contribute to anticipating cardiovascular and metabolic disease phenotypes already in children and young adults. A deeper understanding of environmental factors and their effects on the epigenetic machinery and transcriptional programs is warranted to develop effective mechanism-based therapeutic strategies. The clinical application of epigenetic drugs-also known as "epi-drugs"-is currently exploding in the field of cardiovascular disease. The present review describes the main epigenetic networks underlying cardiometabolic alterations and sheds light on specific points of intervention for pharmacological reprogramming in this setting.


Assuntos
Doenças Cardiovasculares/genética , Endotélio Vascular/metabolismo , Epigênese Genética , Síndrome Metabólica/genética , Animais , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Epigênese Genética/efeitos dos fármacos , Interação Gene-Ambiente , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Fatores de Risco , Transdução de Sinais
10.
BMC Med Genet ; 21(1): 160, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807123

RESUMO

BACKGROUND: Diabetes is mostly assessed by the fasting glucose level. Several studies reported that serum fasting glucose levels and cardiovascular disease are associated with MC4R. METHODS: A total of 4294 subjects participated in this study. There were 1810 subjects with cardiovascular disease among the 4294 subjects. We used multivariate linear regression models and multiple logistic regression analysis. RESULTS: Individuals with the TC/CC genotype had a 1.29-fold higher risk of diabetes than did those with the TT genotype when adjusting for age, sex, and BMI (OR, 1.29; 95% CI, 1.04-1.60). For healthy subjects, the association was significant in women (OR, 1.99; 95% CI, 1.01-3.93). Men with the TC/CC genotype had a 1.21-fold higher risk of cardiovascular disease than did those with the TT genotype when adjusting for age, sex, and BMI (OR, 1.21; 95% CI, 1.04-1.41). The relationship between MC4R and cardiovascular disease was stronger in lean men (OR, 1.40; 95% CI, 1.12-1.74, p = 0.0028) than in overweight men. CONCLUSIONS: This study suggests that the rs17782313 SNP in MC4R is related to diabetes and the SNP is also associated with cardiovascular disease in lean men.


Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 4 de Melanocortina/genética , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Razão de Chances , República da Coreia
11.
Nature ; 584(7822): 589-594, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32814899

RESUMO

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.


Assuntos
Doenças Cardiovasculares/genética , Fractais , Predisposição Genética para Doença , Coração/anatomia & histologia , Coração/fisiologia , Miocárdio/metabolismo , Adulto , Idoso , Animais , Doenças Cardiovasculares/fisiopatologia , Citoesqueleto/genética , Citoesqueleto/fisiologia , Técnicas de Inativação de Genes , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Coração/embriologia , Hemodinâmica , Humanos , Pessoa de Meia-Idade , Miocárdio/citologia , Oryzias/embriologia , Oryzias/genética , Fenótipo
13.
Am J Hum Genet ; 107(2): 211-221, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32649856

RESUMO

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.


Assuntos
Plaquetas/fisiologia , Doenças Cardiovasculares/genética , Receptores de Trombina/genética , Transdução de Sinais/genética , Trombina/genética , Alelos , Embolia/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Insuficiência Cardíaca/genética , Humanos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Receptor PAR-1/genética , Acidente Vascular Cerebral/genética
14.
Nutr Metab Cardiovasc Dis ; 30(10): 1609-1621, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32682747

RESUMO

BACKGROUND AND AIMS: Studies of twins can reduce confounding and provide additional evidence about the causes of disease, due to within-pair matching for measured and unmeasured factors. Although findings from twin studies are typically applicable to the general population, few studies have taken full advantage of the twin design to explore the developmental origins of cardiometabolic health outcomes. We aimed to systematically review the evidence from twin studies and generate pooled estimates for the effects of early-life risk factors on later-life cardiometabolic health. METHODS AND RESULTS: An initial search was conducted in March 2018, with 55 studies of twins included in the review. Risk of bias was assessed using the Newcastle-Ottawa Scale, and eligible studies were included in a meta-analysis, where pooled estimates were calculated. Twenty-six studies analysed twins as individuals, and found that higher birthweight was associated with lower SBP (ß = -2.02 mmHg, 95%CI: -3.07, -0.97), higher BMI (ß = 0.52 kg/m2, 95%CI: 0.20, 0.84) and lower total cholesterol (ß = -0.07 mmol/L, 95%CI: -0.11, -0.04). However, no associations were reported in studies which adjusted for gestational age. Few of the included studies separated their analyses into within-pair and between-pair associations. CONCLUSIONS: Early-life risk factors were associated with cardiometabolic health outcomes in twin studies. However, many estimates from studies in this review were likely to have been confounded by gestational age, and few fully exploited the twin design to assess the developmental origins of cardiometabolic health outcomes.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças em Gêmeos/etiologia , Doenças Metabólicas/etiologia , Gêmeos , Adiposidade , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Peso ao Nascer , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Criança , Pré-Escolar , Colesterol/sangue , Doenças em Gêmeos/sangue , Doenças em Gêmeos/genética , Doenças em Gêmeos/fisiopatologia , Feminino , Idade Gestacional , Nível de Saúde , Humanos , Insulina/sangue , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/genética , Doenças Metabólicas/fisiopatologia , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de Risco , Estudos em Gêmeos como Assunto , Adulto Jovem
15.
PLoS Genet ; 16(7): e1008785, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628676

RESUMO

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.


Assuntos
Doenças Cardiovasculares/genética , Análise da Randomização Mendeliana , Proteoma/genética , Esquizofrenia/genética , Antígenos de Diferenciação/genética , Doenças Cardiovasculares/patologia , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Fator 5 de Crescimento de Fibroblastos/genética , Estudos de Associação Genética/métodos , Humanos , Lipase Lipoproteica/genética , Linfotoxina-alfa/genética , Masculino , Locos de Características Quantitativas , Receptores Imunológicos/genética , Receptores de Interleucina-6/genética , Esquizofrenia/patologia
16.
Rev Cardiovasc Med ; 21(2): 253-261, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32706213

RESUMO

It is known that functional defects of GATA binding protein 5 (GATA5), an important member of GATA transcription factor family, could cause multiple congenital defects. However, the mechanisms of this transcription factor in cardiovascular diseases are still little known. Finding a genetic approach should help with understanding the possible roles of GATA5 in different cardiovascular diseases and purpose it as a possible therapeutic agent. Hence, this review is divided into three chapters to summarize the roles and main regulatory mechanisms of GATA5 in hypertension, arrhythmia and congenital heart disease, respectively. In each chapter, this review firstly introduces the roles of GATA5 mutations, and then discusses the main regulatory mechanisms of GATA5 in the corresponding diseases (Such as the endothelial dysfunction signaling pathway in the chapter of hypertension, GATA5-NaV1.5 signaling pathway in the chapter of arrhythmia, GATA5-HEY2 and GATA5-Nodal signaling pathway in the chapter of congenital heart disease). Additionally, based on these regulatory networks, it is also speculated that abnormal methylation of the GATA5 gene promoter may lead to cardiovascular diseases such as congenital heart disease. This conjecture is proposed to enrich the regulatory networks of GATA5 and provide a theoretical basis for diagnosis and treatment of cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Fator de Transcrição GATA5/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Fator de Transcrição GATA5/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais
17.
Arch Cardiovasc Dis ; 113(8-9): 564-571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32680738

RESUMO

The mitochondria produce specific peptides-mitochondrial-derived peptides-that mediate the transcriptional stress response by their translocation into the nucleus and interaction with deoxyribonucleic acid. Mitochondrial-derived peptides are regulators of metabolism. This class of peptides comprises humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides (SHLPs). Humanin inhibits mitochondrial complex 1 activity and limits the level of oxidative stress in the cell. Data show that mitochondrial-derived peptides have a role in improving metabolic diseases, such as type 2 diabetes. Perhaps humanin can be used as a marker for mitochondrial function in cardiovascular disease or as a pharmacological strategy in patients with endothelial dysfunction. The goal of this review is to discuss the newly emerging functions of humanin, and its biological role in cardiovascular disorders.


Assuntos
Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/metabolismo , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mitocôndrias/genética , Estresse Oxidativo , Transdução de Sinais , Regulação para Cima
18.
Vasc Health Risk Manag ; 16: 249-256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612360

RESUMO

Background: The role of metabolic states in cardiovascular risks among individuals with varying degrees of obesity is unknown. The study aimed to compare cardiometabolic index (CMI), atherogenic index of plasma (AIP), lipid accumulation product (LAP) and novel anthropometric indices in metabolic and non-metabolically obese individual with regard to the role of FTO gene in Iranian adults. Methods: In total, 165 individuals were recruited into this cross-sectional study. Individuals grouped into four groups: metabolic healthy normal-weight (MHNW) individuals, metabolically unhealthy normal-weight (MUNW) individuals, metabolically healthy obese (MHO) individuals and metabolic unhealthy obese (MUO) individuals. The dietary intake was evaluated by food frequency questionnaire (FFQ). The cardiovascular indices (CMI, AIP and LAP) were calculated. A variety of anthropometric indices were calculated, including body adiposity Index (BAI), weight-adjusted-waist index (WWI), A body shape index (ABSI) and waist-height ratio (WHR). The genotypes of FTO-rs9939609 subjects were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The individuals with metabolically unhealthy phenotypes (MUO, MUNW) have higher levels of triglyceride and cardiovascular indices (AIP, LAP and CMI) than the individuals with metabolic healthy phenotypes (MHO, MHNW). With a similar degree of obesity, the anthropometric indices (BAI, WWI and WHR) levels were higher in metabolic unhealthy groups than metabolically healthy groups. The highest frequency of obesity-risk allele AA of FTO gene was observed in MUO, MHO, MUNW and MHNW, respectively. Conclusion: Normal-weight individuals with metabolic unhealthy status are at higher risk for cardiovascular diseases than obese individuals with metabolically healthy status. The genotype frequencies of obesity-risk allele AA of FTO gene were higher in obesity phenotypes than metabolic phenotypes.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Doenças Cardiovasculares/genética , Metabolismo Energético/genética , Síndrome Metabólica/genética , Obesidade Metabolicamente Benigna/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Antropometria , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/diagnóstico , Obesidade Metabolicamente Benigna/sangue , Obesidade Metabolicamente Benigna/diagnóstico , Fenótipo , Medição de Risco , Fatores de Risco , Adulto Jovem
19.
Nature ; 584(7819): 136-141, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581363

RESUMO

Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer1-9. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes1,2,5,6,9, but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank10. We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL) or duplicated them to the homologous chromosome (at FH, NBN, MRE11, ATM, SH2B3 and TM2D3). Three of the genes (MRE11, NBN and ATM) encode components of the MRN-ATM pathway, which limits cell division after DNA damage and telomere attrition11-13; another two (MPL and SH2B3) encode proteins that regulate the self-renewal of stem cells14-16. In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.


Assuntos
Evolução Clonal/genética , Células Clonais/metabolismo , Hematopoese/genética , Herança Multifatorial/genética , Adulto , Idoso , Alelos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Divisão Celular/genética , Aberrações Cromossômicas , Células Clonais/citologia , Células Clonais/patologia , Feminino , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Mosaicismo , Reino Unido
20.
Am J Physiol Heart Circ Physiol ; 319(2): H282-H305, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32559138

RESUMO

Ambient air, occupational settings, and the use and distribution of consumer products all serve as conduits for toxicant exposure through inhalation. While the pulmonary system remains a primary target following inhalation exposure, cardiovascular implications are exceptionally culpable for increased morbidity and mortality. The epidemiological evidence for cardiovascular dysfunction resulting from acute or chronic inhalation exposure to particulate matter has been well documented, but the mechanisms driving the resulting disturbances remain elusive. In the current review, we aim to summarize the cellular and molecular mechanisms that are directly linked to cardiovascular health following exposure to a variety of inhaled toxicants. The purpose of this review is to provide a comprehensive overview of the biochemical changes in the cardiovascular system following particle inhalation exposure and to highlight potential biomarkers that exist across multiple exposure paradigms. We attempt to integrate these molecular signatures in an effort to provide direction for future investigations. This review also characterizes how molecular responses are modified in at-risk populations, specifically the impact of environmental exposure during critical windows of development. Maternal exposure to particulate matter during gestation can lead to fetal epigenetic reprogramming, resulting in long-term deficits to the cardiovascular system. In both direct and indirect (gestational) exposures, connecting the biochemical mechanisms with functional deficits outlines pathways that can be targeted for future therapeutic intervention. Ultimately, future investigations integrating "omics"-based approaches will better elucidate the mechanisms that are altered by xenobiotic inhalation exposure, identify biomarkers, and guide in clinical decision making.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Sistema Cardiovascular/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Material Particulado/efeitos adversos , Adaptação Fisiológica , Adolescente , Adulto , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Reprogramação Celular , Epigênese Genética , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Camundongos , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Medição de Risco , Fatores de Risco , Adulto Jovem
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