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1.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
2.
J Strength Cond Res ; 33(4): 1119-1129, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30908459

RESUMO

Montrezol, FT, Marinho, R, Mota, GdFAd, D'almeida, V, de Oliveira, EM, Gomes, RJ, and Medeiros, A. ACE gene plays a key role in reducing blood pressure in the hyperintensive elderly after resistance training. J Strength Cond Res 33(4): 1119-1129, 2019-Hypertension is a difficult disease to control and exercise training plays a key role in hypertension control. Some individuals are not responsive to exercise training; so, we highlight the polymorphism of I allele of angiotensin-converting enzyme (ACE) as a factor responsible for this lack of responsiveness. The aim of this study was to evaluate the influence of ACE insertion/deletion genotypes on effects of resistance training on blood pressure (BP) and chronic inflammation. Eighty-six hypertensive volunteers, aged between 60 and 80, were evaluated. They performed 16 weeks of resistance training at 50% of 1 maximal repetition. The greatest benefits were seen on homozygous of the Insertion allele, whom presented reduction of systolic blood pressure (SBP: 129.31 ± 13.34 vs. 122.56 ± 9.68 mm Hg, p < 0.001) and diastolic blood pressure (DBP: 79.18 ± 8.05 vs. 70.12 ± 7.71 mm Hg, p < 0.01) during daytime period, and in 24-hour period (SBP: 127.12 ± 13.65 vs. 121.06± 9.68 mm Hg, p < 0.001 and DBP: 71.87 ± 8.39 vs. 68.75 ± 8.72 mm Hg, p < 0.05) and also increased circulating adiponectin levels (4.04 ± 1.79 vs. 6.00 ± 2.81 ng·ml, p < 0.01). Other genotypes showed no changes in BP and biochemical parameters. Our results suggest a cardio protective factor of I allele because only those homozygous showed reductions in BP and increases in adiponectin.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/genética , Treinamento de Resistência , Adiponectina/sangue , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença Crônica , Exercício/fisiologia , Feminino , Homozigoto , Humanos , Hipertensão/sangue , Mutação INDEL , Inflamação/sangue , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
3.
Biomed Res Int ; 2019: 5049746, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30792992

RESUMO

The stroke-prone spontaneously hypertensive rat (SHRSP) suffers from severe hypertension and hypertensive organ damage such as cerebral stroke and kidney injury under salt-loading. By a quantitative trait locus (QTL) analysis between SHRSP and SHR (the stroke-resistant parental strain of SHRSP), two major QTLs for stroke susceptibility were identified on chromosomes 1 and 18 of SHRSP, which were confirmed in congenic strains constructed between SHRSP and SHR. As the progression of renal dysfunction was suggested to be one of the key factors inducing stroke in SHRSP, we examined effects of the stroke-related QTLs on kidney injury using two congenic strains harboring either of SHRSP-derived fragments of chromosomes 1 and 18 in the SHR genome. The congenic strains were challenged with 1% NaCl solution for 4 weeks; measurement of systolic blood pressure and urinary isoprostane level (a marker for oxidative stress) and evaluation of renal injury by quantification of genetic marker expression and histological examination were performed. We found that the congenic rats with SHRSP-derived fragment of chromosome 18 showed more severe renal damage with higher expression of Col1α-1 (a genetic marker for renal fibrosis) and higher urinary isoprostane level. In contrast, the fragment of chromosome 1 from SHRSP did not give such effects on SHR. Blood pressure was not greater in either of the congenic strains when compared with SHR. We concluded that the QTL region on chromosome 18 might deteriorate salt-induced renal injury in SHR through a blood pressure-independent mechanism.


Assuntos
Lesão Renal Aguda/genética , Hipertensão/genética , Locos de Características Quantitativas/genética , Acidente Vascular Cerebral/genética , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Pressão Sanguínea/genética , Colágeno Tipo I/genética , Modelos Animais de Doenças , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Rim/patologia , Ratos , Ratos Endogâmicos SHR/genética , Cloreto de Sódio/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia
4.
Biomed Res Int ; 2019: 9326896, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809549

RESUMO

Angiotensin II plays important functions in cardiovascular system mediating actions leading to inflammatory responses such as activation of VSMC in order to produce ROS, inflammatory cytokines, chemokines, and adhesion molecules. Changes in angiotensin II production could stimulate the recruitment and activation of myeloid cells initiating local inflammatory response without effect on BP. We aimed to verify if angiotensin II induces an inflammatory response in the aorta and if it correlates with variations in BP. C57Bl/6 mice treated with saline solution (0.9%, control group) or angiotensin II (30ng/kg, Ang II group) were used. BP and HR levels were measured. Immunohistochemistry for IL1-ß, TGF-ß, iNOS, CD45, and α-actin was performed in the aorta. BP and HR do not change. A biphasic response was observed both for IL1-ß and TGF-ß expression and also for the presence of CD45 positive cells, with an acute increase (between 30 and 60 minutes) and a second increase, between 24 and 48 hours. Positive staining for iNOS increased in the earlier period (30 minutes) in perivascular adipose tissue and in a longer period (48 hours) in tunica adventitia. Immunoblotting to α-actin showed no alterations, suggesting that the applied dose of angiotensin II does not alter the aortic VSMCs phenotype. The results suggest that angiotensin II, even at doses that do not alter BP, induces the expression of inflammatory markers and migration of inflammatory cells into the aorta of normotensive mice. Thus, angiotensin II may increase the propensity to develop a cardiovascular injury, even in normotensive individuals.


Assuntos
Angiotensina II/administração & dosagem , Aorta/efeitos dos fármacos , Pressão Sanguínea/genética , Doenças Cardiovasculares/genética , Actinas/genética , Angiotensina II/efeitos adversos , Animais , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Antígenos Comuns de Leucócito/genética , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Solução Salina/administração & dosagem , Fator de Crescimento Transformador beta/genética
5.
Genet Epidemiol ; 43(4): 402-413, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30770579

RESUMO

Hypertension is a complex disorder caused by genetic and environmental risk factors. Recently, genome-wide association studies (GWASs) identified more than 100 genetic variants for blood pressure traits and hypertension. However, the interactions between these genetic variants and environmental factors have not been systematically investigated. Therefore, we examined the interaction between genetic and environmental risk factors in blood pressure traits using the genetic risk score (GRS). Two Korean community-based cohorts, Cohort I (KARE; N = 8,840) and Cohort II (CAVAS; N = 9,599), were used for this study, and GRSs were calculated from 42 GWAS single-nucleotide polymorphisms (SNPs) that were validated for their association in these cohorts. We calculated GRSs in both ways by considering the effect sizes of each SNP (weighted GRS) and not considering the effect sizes (unweighted GRS). The unweighted GRS was strongly associated with systolic blood pressure, diastolic blood pressure, and hypertension (p = 9.03 × 10 -47 , p = 9.41 × 10 -48 , and p = 3.22 × 10 -55 by meta-analysis, respectively) and the weighted GRS showed the similar results. The environmental factors of body mass index, waist circumference, and drinking status were significantly associated with blood pressure traits, and the interaction between these factors and GRSs were examined. However, no interactions were found with either the GRS or the individual SNPs considered for the GRS. Our findings show that it is challenging to find GRS-environment interactions regarding blood pressure traits.


Assuntos
Pressão Sanguínea/genética , Interação Gene-Ambiente , Hipertensão/etnologia , Hipertensão/genética , Característica Quantitativa Herdável , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , República da Coreia/epidemiologia , Características de Residência/estatística & dados numéricos , Fatores de Risco
6.
High Blood Press Cardiovasc Prev ; 26(2): 143-144, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30806948

RESUMO

Trisomy of the short arm of chromosome 12 is a rare genetic disease characterised by dysmorphic features, mental retardation, behavioural disorders, seizures predisposition and other congenital abnormalities. Arterial hypertension is not a characteristic feature of 12p trisomy, although congenital heart defects are reported. In this case report, we present a young patient with incomplete trisomy 12p, analysing some characteristics of this disease that have not been previously described in literature.


Assuntos
Pressão Sanguínea/genética , Dislipidemias/complicações , Hipertensão/genética , Trissomia/genética , Adolescente , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cromossomos Humanos Par 12/genética , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Predisposição Genética para Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Lipídeos/sangue , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Trissomia/diagnóstico
7.
Diab Vasc Dis Res ; 16(1): 13-21, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789093

RESUMO

OBJECTIVES: The aim of this study is to explore the contribution of genetically driven cardiometabolic risk factors for development of carotid arterial thickening in patients with type 2 diabetes. METHODS: In total, 12 genetic risk scores for blood pressure, blood lipids and glycaemic traits were constructed. The genetic risk scores were tested for association with carotid intima-media thickness and plaques in patients with type 2 diabetes ( n = 401) and in non-diabetic individuals ( n = 648) and for association with glucose levels in two population-based cohorts ( n = 1328 and n = 6161). RESULTS: In patients with type 2 diabetes, the genetic risk scores for pulse pressure were positively associated with plaque formation ( ß = 0.036 ± 0.01 standard deviation/allele, p = 0.003). The genetic risk score for diastolic blood pressure was negatively associated with carotid intima-media thickness ( ß = -0.037 ± 0.01 standard deviation/allele, p = 0.005), although not significant after correction for multiple testing ( p < 0.0042). In a meta-analysis of individuals with and without type 2 diabetes, the high-density lipoprotein genetic risk scores showed a trend towards an inverse association with carotid intima-media thickness and plaques, while the low-density lipoprotein genetic risk scores showed a trend towards a positive association with plaque formation but did reach the statistical threshold. CONCLUSION: Genetic loci for pulse pressure are associated with plaque formation among patients with type 2 diabetes, suggesting an underlying genetic contribution to arterial stiffening and atherosclerosis.


Assuntos
Pressão Sanguínea/genética , Doenças das Artérias Carótidas/genética , Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2/genética , Hipertensão/genética , Placa Aterosclerótica , Locos de Características Quantitativas , Característica Quantitativa Herdável , Idoso , Doenças das Artérias Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco
8.
J Renin Angiotensin Aldosterone Syst ; 20(1): 1470320319827205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30798697

RESUMO

INTRODUCTION:: This study aimed to investigate whether mononucleotide polymorphisms of the angiotensinogen gene at promoter were associated with the blood-pressure-lowering response to telmisartan treatment. MATERIALS AND METHODS:: After a two-week single-blind placebo run-in period, 148 patients with mild-to-moderate primary hypertension received monotherapy with 80 mg/day of telmisartan and then were followed up for eight weeks. The -6A/G and -20A/C polymorphisms of the angiotensinogen gene at promoter were determined through polymerase chain reaction and restriction fragment length polymorphsim analysis. The relationship between these polymorphisms and changes in blood pressure was observed and evaluated after eight weeks of treatment. RESULTS:: There were no significant differences between -6A/G, -20A/C polymorphisms of the angiotensinogen gene and blood pressure reductions after treatment, p>0.05. CONCLUSION:: It is suggested that angiotensinogen-6 A/G and angiotensinogen-20 A/C polymorphisms were not associated with the antihypertensive response to telmisartan treatment in Chinese patients with hypertension.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Angiotensinogênio/genética , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Hipertensão/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Adulto Jovem
9.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
10.
Hum Genet ; 138(2): 199-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30671673

RESUMO

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 16/genética , Exoma , Ligação Genética , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Processamento Alternativo/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Processamento de RNA/genética , Recombinases/genética
11.
Gene ; 689: 161-165, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30529101

RESUMO

Young-onset hypertensives (YOHs) with resistant hypertension (RH) have a greater long-term cardiovascular risk. The present study examined whether a functional adiponectin T94G polymorphism (rs2241766) is associated with RH in YOHs. We analyzed data from the Academia Sinica Collaborative Study on Hypertension Genetics in Taiwanese subjects to compare rs2241766 between YOHs with and without RH (≤50 years of age). RH was defined as the need for at least 3 drugs, including a diuretic to control blood pressure. Genotyping of rs2241766 was performed using TaqMan allelic discrimination. A total of 861 YOHs were enrolled and 54 had RH in enrolled population. For the rs2241766 in the allelic model, the odds ratio (OR) of RH allele frequency was 2.45 (p = 0.008), and there was a linear relationship between allele numbers and the presence of RH (p = 0.005). In multivariate analysis, the rs2241766 (OR = 2.766, p = 0.002), age (OR = 1.103, p = 0.001), uric acid (OR = 1.322, p = 0.001), high-sensitivity C-reactive protein (OR = 2.769, p = 0.001) and aldosterone (OR = 1.004, p = 0.001) were independently associated with the presence of RH. In the Taiwanese population, the adiponectin T94G polymorphism (rs2241766) is associated with RH in YOHs.


Assuntos
Adiponectina/genética , Resistência a Medicamentos/genética , Hipertensão/tratamento farmacológico , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Pressão Sanguínea/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologia , Adulto Jovem
12.
Hum Antibodies ; 27(2): 99-104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30594920

RESUMO

BACKGROUND: Conventional coronary artery disease (CAD) is the leading cause of morbidity and mortality in the general population. In recent years, multiple CAD promising risk factors have been reported and used for risk stratification. Lipoprotein(a) [LPA] concentration in plasma was shown associated with CAD risk and LPA genetic variants in different ethnic groups remains less clear. METHODS: We obtained data from 100 affected patients with established CAD and 100 healthy controls. We tested Body mass index (BMI), total cholesterol level (TC), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), fasting blood sugar (FBS) and two LPA (rs10455872 and rs3798220 SNPs) between cases and healthy controls. TaqMan SNP genotyping assays were performed to detect variants. RESULTS: Obtained data for BMI, TC, SBP, DBP, and LDL have significantly difference between two groups. Individually, the single SNPs were not associated with CAD in different analysis models. Also there was no significant difference in the incidence of CAD among cases carrying different genotypes of the two variants in LPA with p> 0.05. DISCUSSION: In this study patients with CAD, lipoprotein(a) concentrations and genetic variants showed no associations and we conclude that these variables are not useful risk factors to predict progression to disease is Iranian population. However, the prevalence and association of LPA SNPs with size of LPA and isoforms are highly variable and genetic background-specific. CONCLUSION: Our data did not indicate a relationship between genomic LPA variants (rs10455872 and rs3798220) and subsequent cardiovascular events in Iranian CAD patients. We did not confirm the association of the theses SNPs with CAD in our samples of Iranian patients. For the studied variants, our finding is consistent with reports which showed the lack of this genetic association in other populations.


Assuntos
Doença da Artéria Coronariana/genética , Predisposição Genética para Doença/genética , Lipoproteína(a)/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Glicemia/genética , Pressão Sanguínea/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Colesterol/sangue , Feminino , Genótipo , Humanos , Irã (Geográfico) , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
13.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
14.
BMC Cardiovasc Disord ; 18(1): 237, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547758

RESUMO

BACKGROUND: Klotho, possibly an age-regulating protein, is considered an important factor contributing to the lifespan and pathophysiology of hypertension and coronary artery disease (CAD). The present study was carried out aiming to investigate the association of Klotho-rs564481 (C1818T) gene polymorphism with hypertension and CAD. METHODS: A total of 286 CAD-suspicious subjects were entered into this case-control study. The polymorphism was investigated in hypertensive patients with no CAD (H-Tens, n = 60); hypertensive patients with CAD (CAD + H-Tens, n = 95); CAD patients with no hypertension (CAD, n = 61); and non-hypertensive non-CAD subjects, which were regarded as the control group (Ctrl, n = 70). Genotype and allele frequencies were assessed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: A significant difference was found in allele frequency of Klotho C1818T among the four research groups (P = 0.03). It was also found that wild-type homozygote subjects were negatively associated with hypertension as compared to heterozygote ones (OR = 0.07 [95% CI: 0.008-0.69] P = 0.02). Moreover, in the subgroups older than 57 years old, dominant genetic model demonstrated a negative association with CAD combined with hypertension (OR = 0.31 [95% CI: 0.10-0.95] P = 0.04). CONCLUSIONS: In conclusion, Klotho C1818T variant may be associated with a decreased risk of hypertension. Moreover, aging enhanced positive effects of the Klotho polymorphism on CAD combined with hypertension, indicating the possibility that the KLOTHO gene might play a part in the age-related occurrence of CAD combined with hypertension.


Assuntos
Doença da Artéria Coronariana/genética , Glucuronidase/genética , Hipertensão/genética , Polimorfismo Genético , Adulto , Fatores Etários , Idoso , Pressão Sanguínea/genética , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco
15.
Medicine (Baltimore) ; 97(42): e12917, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30335025

RESUMO

Angiotensin-converting enzyme 2 (ACE2) plays an important role in the development of essential hypertension (EH). The aim of this study was to investigate the relationship of ACE2 gene polymorphisms and enzymatic activity with EH in the northeastern Chinese Han population. 34 single-nucleotide polymorphism (SNP) loci of ACE2 were detected in 1024 EH patients and 956 normotensive (NT) controls by Sequenom Mass-ARRAY RS1000. Five SNPs (rs1514283, rs4646155, rs4646176, rs2285666, and rs879922) in ACE2 gene were determined to significantly associate with EH in female participants, while no SNP locus was linked to male group. Specifically, it was the first time to report that rs4646155 was significantly associated with EH in females. Furthermore, the correlation between ACE2 activity and clinical parameters were performed by Pearson correlation analysis in EH patients. We found that the ACE2 activity level was negatively correlated with body mass index (BMI), DBP, and pulse pressure, and significantly positively with ACE2 concentration, blood glucose and estrogen level in female EH patients. These results demonstrated that the genetic variants of ACE2 played vital roles in the development of EH. And the serum ACE2 activity can predict the development of cardiac dysfunction in EH patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipertensão Essencial/genética , Peptidil Dipeptidase A/sangue , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Idoso , Pressão Sanguínea/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/genética
16.
Medicine (Baltimore) ; 97(33): e11865, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30113482

RESUMO

Rare variants, in particular renal salt handling genes, contribute to monogenic forms of hypertension and hypotension syndromes with electrolyte abnormalities. A study by Ji et al (2008) demonstrated this effect for rare loss-of-function coding variants in SLC12A3 (NCCT), SLC12A1 (NKCC2), and KCNJ1 (ROMK) that led to reduction of ∼6 mm Hg for SBP and ∼3 mm Hg for DBP among carriers in 2492 European ancestry Framingham Heart Study (FHS) subjects. These findings support a potentially large role for these variants in interindividual variation in systolic and diastolic blood pressure (SBP, DBP) in the population. The present study focuses on replicating the analyses completed by Ji et al to identify effects of rare variants in the population-based Atherosclerosis Risk in Communities (ARIC) study.We attempted to replicate the findings by Ji et al by applying their criteria to identify putative loss-of-function variants with allele frequency <0.001 and complete conservation across a set of orthologs, to exome sequencing data from 7444 European ancestry participants of the ARIC study.Although we failed to replicate the previous findings when applying their methods to the ARIC study data, we observed a similar effect when we restricted analyses to the subset of variants they observed.These results simultaneously support the utility of exome sequencing data for studying extremely rare coding variants in hypertension and underscore the need for improved filtering methods for identifying functional variants in human sequences.


Assuntos
Hipertensão/genética , Hipotensão/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Membro 1 da Família 12 de Carreador de Soluto/genética , Grupo com Ancestrais do Continente Africano/genética , Pressão Sanguínea/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Membro 3 da Família 12 de Carreador de Soluto/genética , Sequenciamento Completo do Exoma
17.
Gene ; 677: 245-250, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30059752

RESUMO

OBJECTIVES: High-salt diet is one of the major risk factors in the development of hypertension. Previous studies have observed a relationship between high-salt induced blood pressure levels and cardiac-cerebral disease. However, the molecular mechanism of high-salt diet induced hypertension and the serious complications in cardiovascular system still remain unknown. MATERIALS AND METHODS: We built high-salt diet induced hypertension rat models, and investigated the transcriptomic alteration in four hypertension affected tissues, i.e. ventricle and atrium in heart as well as cortex and medulla in kidney. Differential expression gene (DEG) analysis and further functional annotation including Ingenuity Pathway Analysis (IPA) was performed to reveal the molecular mechanism of high-salt induced hypertension and organ injury. RESULTS: We observed that several genes associated with cardiovascular development and organ injury were significantly dysregulated rat fed with high-salt diet, such as Mmp-15, Igfbp7, Rgs18 and Hras. We demonstrated that differential expressed genes were functionally related to the increased levels of alkaline phosphatase (ALP). CONCLUSION: Our study provided new insight about molecular mechanism of high-salt induced hypertension and heart and kidney damage.


Assuntos
Hipertensão/genética , RNA/genética , Cloreto de Sódio/farmacologia , Animais , Pressão Sanguínea/genética , Dieta/métodos , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Nefropatias/genética , Masculino , Ratos , Ratos Sprague-Dawley
18.
Gene ; 677: 176-181, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30053459

RESUMO

BACKGROUND: The correlation between single nucleotide polymorphisms (SNPs) of milk fat globule-epidermal growth factor 8 (MFGE8) and metabolic syndrome (MetS) and metabolism-related indicators are limited. The present study explored the relation in Chinese adults. METHODS: We conducted a nested case-control study based on the Rural Chinese Cohort Study including 408 people with MetS and 408 controls matched by baseline sex, age (±2 years), marital status, and residence village. Four polymorphisms were selected and genotyped by using the SNPscan Genotyping system. Conditional logistic regression was used to estimate the association of MFGE8 polymorphisms with MetS incidence, and linear regression was used to assess the association with metabolism-related indicators in controls. RESULTS: We found no significant association of MFGE8 SNPs with MetS incidence or systolic blood pressure, or triglycerides level, or fasting plasma glucose (P > 0.05). However, MFGE8 rs4932450 was negatively associated with high-density lipoprotein cholesterol (HDL-C) level under the dominant model (ß = -0.0218, P = 0.007) and the additive model (ß = -0.0175, P = 0.012) and positively associated with diastolic blood pressure (DBP) under the recessive model (ß = 4.8848, P = 0.011). The rs3784751 SNP was associated with increased waist circumference (WC) in controls (ß = 0.0307, P = 0.028). CONCLUSIONS: MFGE8 polymorphisms were not associated with MetS but were related to DBP, HDL-C level, and WC in Chinese adults.


Assuntos
Antígenos de Superfície/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Síndrome Metabólica/genética , Proteínas do Leite/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Pressão Sanguínea/genética , Estudos de Casos e Controles , HDL-Colesterol/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Triglicerídeos/sangue , Circunferência da Cintura/genética
19.
J Renin Angiotensin Aldosterone Syst ; 19(2): 1470320318782622, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29923443

RESUMO

OBJECTIVE: Polymorphisms of the renin angiotensin system (RAS) are associated with increases in blood pressure (BP). Physical exercise has been considered the main strategy to prevent this increase. This study aimed to investigate the relationship between estimated training status (TS), BP and angiotensin-converting enzyme (ACE) activity in elderly people classified as low or high risk to develop hypertension according to genetic profile. METHODS: A total of 155 elderly participants performed the following assessments: general functional fitness index (GFFI), systolic BP (SBP) and diastolic BP (DBP), blood collection for ACE activity and analyses of the RAS polymorphisms. RESULTS: Uncontrolled hypertensive (UHT) participants presented higher values of SBP and DBP compared with normotensive (NT) and controlled hypertensive (CHT) participants. No differences were found in ACE activity and GFFI between groups. In the high risk group, UHT presented higher values of SBP and DBP compared with other groups. CHT presented higher values of SBP compared with NT. Furthermore, UHT presented higher values of ACE activity compared with CHT and lower values of GFFI compared with NT. CONCLUSION: MDA, TIA and TIC genetic combinations were associated with high risk of developing hypertension while the maintenance of good levels of TS was associated with lower BP values and ACE activity.


Assuntos
Pressão Sanguínea/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Sistema Renina-Angiotensina/genética , Idoso , Alelos , Feminino , Genótipo , Hemodinâmica , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino
20.
Nutrients ; 10(5)2018 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-29757959

RESUMO

This study was performed to investigate whether genetic variation in the epithelial sodium channel (ENaC) is associated with 24-h urinary sodium excretion and blood pressure. A total of 3345 participants of the KoGES_Ansan and Ansung study were eligible for this study. Genomic DNA samples were isolated from peripheral blood and genotyped on the Affymetrix Genome-Wide Human SNP Array 5.0. Thirty-four single nucleotide polymorphisms (SNPs) were extracted for gene regions (SCNN1A, SCNN1B, and SCNN1G) as additive components by using Plink. Twenty-four-hour sodium excretions were estimated from spot urine samples using the Tanaka formula. The general linear model (GLM) was applied to assess the association between SNPs and urinary sodium excretion or blood pressure. In the SCNN1G gene, six SNPs (rs4073291, rs12934362, rs7404408, rs4494543, rs5735, and rs6497657) were significantly different in 24-h urinary sodium excretion according to gene variants. However, no difference was found in blood pressure among participants with gene variants of ENaC. Our finding indicated that 24-h urinary sodium excretions were different according to variants of the SCNN1G gene in large samples. Further studies to replicate these findings are warranted.


Assuntos
Pressão Sanguínea/genética , Canais Epiteliais de Sódio/genética , Polimorfismo de Nucleotídeo Único , Sódio/urina , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Estudos de Coortes , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos
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