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1.
Medicine (Baltimore) ; 99(40): e22436, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019425

RESUMO

In addition to governing key functions in bone metabolism and the immune system, the RANK/RANKL/OPG system plays a role in the vascular system, particularly in vascular calcification and atherosclerosis.Given that these 2 phenotypes are considered a major cause of high blood pressure (BP), in this study we analyzed the association of SNPs in RANK and OPG genes with blood pressure. An observational study was conducted of 2 SNPs in the RANK gene (rs884205 and rs78326403) and 1 in the OPG gene (rs4876869) with systolic (SBP) and diastolic blood pressure (DBP) in a cohort of 695 women.Data analysis revealed a statistically significant association between the SNP rs884205 and BP pressure (SBP and DBP). Analyzing this relationship by the dominant inheritance model for this SNP (allele risk: A), women of the AA/AC genotype showed higher BP than women of the CC genotype, both for SBP (P = .001) and for DBP (P = .003), and these associations both surpassed the Bonferroni threshold for multiple comparisons. Multivariate regression analysis including known predictors of BP as independent variables was performed to evaluate the strength of this association, which in the case of the SNP rs884205 of the RANK gene remained statistically significant after adjustment for both SBP (P = .0006) and DBP (P = .005), demonstrating the key role of this SNP in BP.We report a robust association between the SNP rs884205 in RANK gene and BP in women, and this SNP is validated as a candidate in cardiovascular risk studies.


Assuntos
Pressão Sanguínea/genética , Receptor Ativador de Fator Nuclear kappa-B/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Osteoprotegerina/sangue , Polimorfismo de Nucleotídeo Único , Espanha
2.
PLoS One ; 15(8): e0237708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817646

RESUMO

Parental high-fat diet (HFD) programs for obesity and hypertension in female offspring in rats, but it is unknown how the pregnancies of these offspring are impacted. Therefore, the hypothesis was tested that parental HFD exaggerates obesity and hypertension during pregnancy of the offspring. Wistar Hannover rat dams (the parental, P generation) were maintained on normal-fat diet (NFD) or HFD from weaning and were kept on respective diets through pregnancy and lactation. Their offspring (the first filial, F1 generation) were weaned onto the same diet as the P generation, or they were changed to the other diet to determine if combined HFD in the P and F1 generations exaggerates body weight and blood pressure levels during pregnancy in these offspring. This diet paradigm resulted in the following groups of pregnant F1 offspring: P-NFD/F1-NFD, P-HFD/F1-NFD, P-NFD/F1-HFD, and P-HFD/F1-HFD. Maternal body and adipose tissue weights were greatest in the P-HFD/F1-HFD group compared to the other 3 groups by the end of pregnancy. Plasma leptin and conscious mean arterial blood pressure were not significantly different between any group, although there was a main effect for increased blood pressure in the F1-HFD groups. Circulating levels of the antihypertensive pregnancy factor, placental growth factor (PlGF), were assessed. Although average PlGF levels were similar among all groups, correlative studies revealed that lower levels of PlGF were associated with higher blood pressure only in the P-HFD/F1-HFD group. In summary, HFD feeding from the P generation exaggerated HFD-induced body and adipose tissue weights in the pregnant offspring.


Assuntos
Hipertensão/sangue , Leptina/sangue , Obesidade/sangue , Fator de Crescimento Placentário/sangue , Efeitos Tardios da Exposição Pré-Natal/sangue , Adiposidade/genética , Animais , Pressão Sanguínea/genética , Peso Corporal/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Herança Materna/genética , Obesidade/genética , Obesidade/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Desmame
3.
PLoS One ; 15(8): e0236968, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745140

RESUMO

Many circumstantial evidences from human and animal studies suggest that complement cascade dysregulation may play an important role in pregnancy associated complications including preeclampsia. Deletion of rodent specific complement inhibitor gene, Complement Receptor 1-related Gene/Protein y (Crry) produces embryonic lethal phenotype due to complement activation. It is not clear if decreased expression of Crry during pregnancy produces hypertensive phenotype. We downregulated Crry in placenta by injecting inducible lentivialshRNA vectors into uterine horn of pregnant C57BL/6 mice at the time of blastocyst hatching. Placenta specific downregulation of Crry without significant loss of embryos was achieved upon induction of shRNA using an optimal doxycycline dose at mid gestation. Crry downregulation resulted in placental complement deposition. Late-gestation measurements showed that fetal weights were reduced and blood pressure increased in pregnant mice upon downregulation of Crry suggesting a critical role for Crry in fetal growth and blood pressure regulation.


Assuntos
Desenvolvimento Fetal/fisiologia , Placenta/metabolismo , Receptores de Complemento 3b/genética , Animais , Pressão Sanguínea/genética , Ativação do Complemento/genética , Complemento C3/metabolismo , Inativadores do Complemento/farmacologia , Feminino , Desenvolvimento Fetal/genética , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos C57BL , Placenta/fisiologia , Pré-Eclâmpsia/genética , Gravidez , RNA Interferente Pequeno/genética , Receptores de Complemento/genética , Receptores de Complemento 3b/metabolismo
4.
Nat Commun ; 11(1): 3368, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632093

RESUMO

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10-06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10-08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10-25) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10-07) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10-07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.


Assuntos
Pressão Sanguínea/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Transtornos de Enxaqueca/genética , Polimorfismo de Nucleotídeo Único , Humanos , Hipertensão/genética , Cadeias beta de Integrinas/genética , Análise da Randomização Mendeliana/métodos , Proteínas/genética , Receptores Adrenérgicos alfa 2/genética , Fatores de Risco , Telomerase/genética
5.
Neurology ; 95(4): e353-e361, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32611631

RESUMO

OBJECTIVE: We employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. METHODS: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH). RESULTS: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not ß-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH. CONCLUSIONS: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/complicações , Hipertensão/genética , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Pressão Sanguínea/genética , Doenças de Pequenos Vasos Cerebrais/etiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana
6.
PLoS One ; 15(7): e0235756, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702059

RESUMO

Genome-wide association studies (GWAS) have routinely detected human quantitative trait loci (QTLs) for complex traits. Viewing that most GWAS single nucleotide polymorphisms (SNPs) are found in non-coding regions unrelated to the physiology of a polygenic trait of interest, a vital question to answer is whether or not any of these SNPs can functionally alter the phenotype with which it is associated. The study of blood pressure (BP) is a case in point. Conserved mechanisms in controlling BP by modularity is now unifying differing mammalian orders in that understanding mechanisms in rodents is tantamount to revealing the same in humans, while overcoming experimental limitations imposed by human studies. As a proof of principle, we used BP QTLs from Dahl salt-sensitive rats (DSS) as substitutes to capture distinct human functional orthologs. 3 DSS BP QTLs are located into distinct genome regions and correspond to several human GWAS genes. Each of the QTLs independently exerted a major impact on BP in vivo. BP was functionally changed by normotensive alleles from each of these QTLs, and yet, the human GWAS SNPs do not exist in the rat. They cannot be responsible for physiological alterations in BP caused by these QTLs. These SNPs are genome emblems for QTLs nearby, rather than being QTLs per se, since they only emerged during primate evolution after BP-regulating mechanisms have been established. We then identified specific mutated coding domains that are conserved between rodents and humans and that may implicate different steps of a common pathway or separate pathways.


Assuntos
Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Hipertensão/genética , Hipertensão/prevenção & controle , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Animais , Determinação da Pressão Arterial , Mapeamento Cromossômico , Humanos , Masculino , Fenótipo , Ratos , Ratos Endogâmicos Dahl
7.
PLoS One ; 15(4): e0232048, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315356

RESUMO

Hypertension occurs at a higher rate in African Americans than in European Americans. Based on the assumption that causal variants are more frequently found on DNA segments inherited from the ancestral population with higher disease risk, we employed admixture mapping to identify genetic loci with excess local African ancestry associated with blood pressure. Chromosomal regions 1q21.2-21.3, 4p15.1, 19q12 and 20p13 were significantly associated with diastolic blood pressure (ß = 5.28, -7.94, -6.82 and 5.89, P-value = 6.39E-04, 2.07E-04, 6.56E-05 and 5.04E-04, respectively); 1q21.2-21.3 and 19q12 were also significantly associated with mean arterial pressure (ß = 5.86 and -6.40, P-value = 5.32E-04 and 6.37E-04, respectively). We further selected SNPs that had large allele frequency differences within these regions and tested their association with blood pressure. SNP rs4815428 was significantly associated with diastolic blood pressure after Bonferroni correction (ß = -2.42, P-value = 9.57E-04), and it partially explained the admixture mapping signal at 20p13. SNPs rs771205 (ß = -1.99, P-value = 3.37E-03), rs3126067, rs2184953 and rs58001094 (the latter three exhibit strong linkage disequilibrium, ß = -2.3, P-value = 1.4E-03) were identified to be significantly associated with mean arterial pressure, and together they fully explained the admixture signal at 1q21.2-21.3. Although no SNP at 4p15.1 showed large ancestral allele frequency differences in our dataset, we detected association at low-frequency African-specific variants that mapped predominantly to the gene PCDH7, which is most highly expressed in aorta. Our results suggest that these regions may harbor genetic variants that contribute to the different prevalence of hypertension.


Assuntos
Afro-Americanos/genética , Pressão Sanguínea/genética , Mapeamento Cromossômico/métodos , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
8.
BMC Med Genet ; 21(1): 83, 2020 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-32306916

RESUMO

BACKGROUND: The role of angiotensin II type 1 receptor (AT1R) as a key player in type 2 diabetes mellitus (T2DM) complicated with hypertension remains controversial. The present case-control study systematically investigated the association between gene the correct variation type in the angiotensin II type 1 receptor (AT1R) gene and type 2 diabetes mellitus complicated with hypertension in the Han population from the Inner Mongolia region, China. METHOD: Here, state which variants were analysis, including age, occupation, triglyceride, systolic, diastolic, sex, culture, marital status, smoking, alcohol, BMI (body mass index), SBP (systolic blood pressure), DBP (diastolic blood pressure), TG (triglyceride), TC (total cholesterol), HDL-C (high-density lipoprotein cholesterol), LDL-C (low-density lipoprotein cholesterol), FPG (fasting plasma glucose). Genomic DNA was extracted from samples from 202 type 2 diabetic patients with hypertension and 216 type 2 diabetic patients without hypertension. RESULTS: Non-conditional regression analysis showed that in comparison with the TT genotype, the presence of the CC genotype for the T573 site of the AT1R gene increased the risk for diabetes mellitus complicated with hypertension by 3.219-fold (OR = 3.219, 95% CI: 1.042-9.941, P = 0.042). The results from multivariate linear regression analysis suggested the rs5182 polymorphism in the AT1R gene to be associated with diastolic blood pressure (P = 0.032). No other associations were found between the incidence of disease and the correct variation type at other sites of the AT1R gene. CONCLUSIONS: Our results suggest that the rs5182 polymorphism in the AT1R gene is associated with diabetes complicated by hypertension in the Han population of Inner Mongolia.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Hipertensão/genética , Receptor Tipo 1 de Angiotensina/genética , Glicemia/genética , Pressão Sanguínea/genética , Índice de Massa Corporal , Estudos de Casos e Controles , China/epidemiologia , HDL-Colesterol/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudos de Associação Genética , Humanos , Hipertensão/etiologia , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Triglicerídeos/genética
9.
Pregnancy Hypertens ; 20: 7-13, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32120336

RESUMO

BACKGROUND: Pre-eclampsia (PE) is a leading cause of maternal and neonatal mortality in Africa; and has been associated with the interplay of genetic, metabolic and environmental factors. Polymorphisms of methylene tetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) folate cycle genes, have been controversially associated with pre-eclampsia in studies from different human populations. OBJECTIVES: To determine the distribution of MTHFR C677T and MTR A2756G polymorphisms in a Nigerian population and evaluate possible associations with the occurrence of pre-eclampsia and homocysteine metabolic derangement. MATERIALS AND METHODS: This study was a hospital based study carried out in Lagos, South-western Nigeria. Two hundred pregnant women clinically diagnosed with pre-eclampsia (study group) and 200 apparently healthy non-pre-eclamptic pregnant women (control group) were recruited for the study after written informed consent. Pre-eclampsia was diagnosed based on the International Society for the Study of Hypertension in Pregnancy re-classification of 2013. MTHFR C677T and MTR A2756G polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistical analyzes were performed using SPSS version 23. Hardy-Weinberg distribution were tested with χ2 test. Logistic regression model was used to evaluate the relationship of variables with pre-eclampsia. A value of p < 0.05 was considered statistically significant. RESULTS: MTHFR genotype frequencies of CC, CT and TT were 59.8%; 31.2% and 9.0% in study group and 76.6%; 22.3% and 1.0% in the control group respectively. MTR A2756G genotype frequencies of AA, AG and GG genotypes were 71.9%; 20.1% and 8.0% for the study group and 81.5%; 16.4% and 2.1% for the control group. Occurrence of pre-eclampsia was significantly associated with presence of T allele of MTHFR (OR = 1.855; p < 0.05) and G allele of MTR genes (OR = 1.269; p < 0.05), Homozygosity of TG haplotype significantly increased the occurrence of pre-eclampsia among Nigerian women (OR = 2.252; p < 0.05). Population attributable risk fraction percent for the T and G alleles were 16.4% and 11.5% respectively. Mean plasma Hcy level was not, however, significantly affected by MTHFR/MTR haplotypes (F = 1.54; p = 0.157). CONCLUSION: MTHFR C677T and MTR A2756G polymorphisms were associated with pre-eclampsia in a population of pregnant women in Lagos, Nigeria.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Pressão Sanguínea/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Homozigoto , Humanos , Nigéria , Fenótipo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Adulto Jovem
10.
Pregnancy Hypertens ; 20: 19-26, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145524

RESUMO

OBJECTIVE: To investigate the relationship between platelet-activating factor acetylhydrolase (PAF-AH) gene (PLA2G7) G994T (V279F, rs76863441) and R92H (rs1805017) polymorphisms and risk of preeclampsia (PE) in Chinese women. STUDY DESIGN: This is a case-control study of 273 patients with PE and 530 healthy pregnant women. MAIN OUTCOME MEASURES: PLA2G7 genotypes were determined by polymerase chain reaction amplification and restriction analysis. Plasma PAF-AH, apolipoprotein (apo) B-containing lipoprotein-associated PAF-AH (apoB-PAF-AH), total high-density lipoprotein (HDL)-associated PAF-AH (H-PAF-AH), apoE-containing HDL-associated PAF-AH (apoE-H-PAF-AH) activities, and clinical, metabolic, and oxidative stress parameters were also analyzed. RESULTS: The frequencies of the GT + TT genotype (14.7 versus 9.2%, P = 0.019) and T allele (7.5% versus 4.6%) of PLA2G7 G994T polymorphism were significantly higher in patients with PE than in the control subjects. The GT + TT genotypes remained a significant predictor for PE in a regression model including age, body mass index (BMI), plasma PAF-AH, H-PAF-AH, apoE-H-PAF-AH and apoB-PAF-AH activities as covariates (odds ratio (OR) = 4.926, 95% confidence interval (CI): 1.707-14.219, P = 0.003). The ratio of apoB-PAF-AH to H-PAF-AH activities was significantly higher, while serum triglyceride levels were lower in patients with the GT genotype compared with patients with the GG genotype (P < 0.05). No significant differences were observed in the frequencies of the R92H genotype and allele between the PE and control groups. CONCLUSIONS: The PLA2G7 G994T, but not R92H, genetic polymorphism is associated with the risk of PE in Chinese women.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Pressão Sanguínea/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Adulto , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Fenótipo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Medição de Risco , Fatores de Risco , Adulto Jovem
11.
Radiat Res ; 193(6): 552-559, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150496

RESUMO

In this work, we utilized spontaneously hypertensive rats (SHR) and Wister Kyoto rats (WKY), from which the SHR was established, to evaluate the effects of whole-body acute radiation on the cardiovascular system at doses from 0 to 4 Gy. In the irradiated SHR, the systolic blood pressure (SBP) increased with increasing dose, while body weight gain decreased with increasing radiation dose. Furthermore, pathological observations of SHR demonstrated that the number of rats with cystic degeneration in the liver increased with increasing dose. The effects observed among SHR, such as increased SBP and retardation of body weight gain, appear very similar to those observed in Japanese atomic bomb survivors. In contrast, the SBP among WKY did not change relative to dose; the body weight, however, did change, as in the SHR. Therefore, the association between radiation exposure and SBP, but not between radiation exposure and retardation of body weight gain, may be affected by genetic background, as evident from strain difference. These results suggest that the SHR and WKY animal models may be useful for studying radiation effects on non-cancer diseases including circulatory diseases, chronic liver disease and developmental retardation.


Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/efeitos da radiação , Peso Corporal/genética , Peso Corporal/efeitos da radiação , Patrimônio Genético , Animais , Fígado/patologia , Fígado/efeitos da radiação , Masculino , Ratos , Ratos Endogâmicos SHR
12.
BMC Med Genet ; 21(1): 44, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111194

RESUMO

BACKGROUND: Abnormal calcium homeostasis related to the development of hypertension. As the key regulator of intracellular calcium concentration, voltage-dependent calcium channels (VDCCs), the variations in these genes may have important effects on the development of hypertension. Here we evaluate VDCCs variability with respect to hypertension in the Dai ethnic group of China. METHODS: A total of 1034 samples from Dai individuals were collected, of which 495 were used as cases, and 539 were used as controls. Blood pressure was measured using a standard mercury measurement method, three times with a rest for 5 min, and the average was used for analyses. Seventeen single nucleotide polymorphisms (SNPs) in the four protein-coding genes (CACNA1A, CACNA1C, CACNA1S, CACNB2) of VDCCs were identified by multiplex PCR-SNP typing technique. Chi-square tests and regression models were used to analyse the associations of SNPs with hypertension. RESULTS: The results of chi-square tests showed that the allele frequencies of 5 SNPs were significantly different between the case and the control groups (P < 0.05), but the statistical significance was lost after Bonferroni's correction. However, after adjusting for BMI, age, sex and other factors by logistic regression analyses, the results showed that 5 SNPs consistent with chi-square tests (rs2365293, rs17539088, rs16917217, rs61839222 and rs10425859) were still statistically positive. CONCLUSIONS: This finding suggested that the significant association of these SNPs with hypertension may be noteworthy in future studies.


Assuntos
Grupo com Ancestrais do Continente Asiático , Canais de Cálcio/genética , Hipertensão/etnologia , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Pressão Sanguínea/genética , Estudos de Casos e Controles , China/epidemiologia , Grupos Étnicos/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
13.
Genet Epidemiol ; 44(3): 300-310, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32048322

RESUMO

Hypertension is a common disease worldwide. Alcohol consumption is one of the risk factors for hypertension, however, it is unclear how alcohol consumption elevates blood pressure. Blood pressure could be affected by interactions between genetic variations and alcohol consumption. Thus, we performed a genome-wide interaction study (GWIS) to assess the effect of gene-alcohol consumption interaction on blood pressure among adults aged ≥40 years from the Ansan and Ansung cohort study (n = 6,176), a part of the Korean Genome Epidemiology Study (KoGES). As a result, rs1297184, single-nucleotide polymorphism (SNP) in locus LGR5 was significant (PGWIS = 8.78 × 10-9 ) in GWIS analysis on diastolic blood pressure, but not on systolic blood pressure. However, there was a heteroscedasticity of alcohol consumption. In the GWIS analysis, applying the inverse-variance weighting to correct the systematic inflation slightly attenuated the strength of interaction (PGWIS_IVW = 7.14 × 10-8 ). This interaction was replicated in the Health Examinees cohort (p = .026), a large-scale community-based cohort (n = 18,708). In conclusion, we identified a possible novel interaction between an SNP (rs1297184) and alcohol consumption on blood pressure.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Pressão Sanguínea/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Estudos de Coortes , Diástole/genética , Feminino , Loci Gênicos , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , República da Coreia/epidemiologia , Fatores de Risco
14.
BMC Med Genomics ; 13(Suppl 3): 26, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093692

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have been widely used to identify phenotype-related genetic variants using many statistical methods, such as logistic and linear regression. However, GWAS-identified SNPs, as identified with stringent statistical significance, explain just a small portion of the overall estimated genetic heritability. To address this 'missing heritability' issue, gene- and pathway-based analysis, and biological mechanisms, have been used for many GWAS studies. However, many of these methods often neglect the correlation between genes and between pathways. METHODS: We constructed a hierarchical component model that considers correlations both between genes and between pathways. Based on this model, we propose a novel pathway analysis method for GWAS datasets, Hierarchical structural Component Model for Pathway analysis of Common vAriants (HisCoM-PCA). HisCoM-PCA first summarizes the common variants of each gene, first at the gene-level, and then analyzes all pathways simultaneously by ridge-type penalization of both the gene and pathway effects on the phenotype. Statistical significance of the gene and pathway coefficients can be examined by permutation tests. RESULTS: Using the simulation data set of Genetic Analysis Workshop 17 (GAW17), for both binary and continuous phenotypes, we showed that HisCoM-PCA well-controlled type I error, and had a higher empirical power compared to several other methods. In addition, we applied our method to a SNP chip dataset of KARE for four human physiologic traits: (1) type 2 diabetes; (2) hypertension; (3) systolic blood pressure; and (4) diastolic blood pressure. Those results showed that HisCoM-PCA could successfully identify signal pathways with superior statistical and biological significance. CONCLUSIONS: Our approach has the advantage of providing an intuitive biological interpretation for associations between common variants and phenotypes, via pathway information, potentially addressing the missing heritability conundrum.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Pressão Sanguínea/genética , Estudos de Coortes , Simulação por Computador , Conjuntos de Dados como Assunto , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hipertensão/genética , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Estatísticos
15.
PLoS One ; 15(1): e0227728, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999706

RESUMO

BACKGROUND: High blood pressure is a major risk factor for cardiovascular disease and is influenced by both environmental and genetic factors. Epigenetic processes including DNA methylation potentially mediate the relationship between genetic factors, the environment and cardiovascular disease. Despite an increased risk of hypertension and cardiovascular disease in individuals of South Asians compared to Europeans, it is not clear whether associations between blood pressure and DNA methylation differ between these groups. METHODS: We performed an epigenome-wide association study and differentially methylated region (DMR) analysis to identify DNA methylation sites and regions that were associated with systolic blood pressure, diastolic blood pressure and hypertension. We analyzed samples from 364 European and 348 South Asian men (first generation migrants to the UK) from the Southall And Brent REvisited cohort, measuring DNA methylation from blood using the Illumina Infinium® HumanMethylation450 BeadChip. RESULTS: One CpG site was found to be associated with DBP in trans-ancestry analyses (i.e. both ethnic groups combined), while in Europeans alone seven CpG sites were associated with DBP. No associations were identified between DNA methylation and either SBP or hypertension. Comparison of effect sizes between South Asian and European EWAS for DBP, SBP and hypertension revealed little concordance between analyses. DMR analysis identified several regions with known relationships with CVD and its risk factors. CONCLUSION: This study identified differentially methylated sites and regions associated with blood pressure and revealed ethnic differences in these associations. These findings may point to molecular pathways which may explain the elevated cardiovascular disease risk experienced by those of South Asian ancestry when compared to Europeans.


Assuntos
Pressão Sanguínea/genética , Ilhas de CpG/genética , Metilação de DNA , Epigenoma/genética , Hipertensão/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Emigrantes e Imigrantes , Epigênese Genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia
16.
Ann Neurol ; 87(4): 516-524, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31975536

RESUMO

OBJECTIVE: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease. METHODS: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively. RESULTS: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (ß = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose. INTERPRETATION: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524.


Assuntos
Transtornos Cerebrovasculares/epidemiologia , Obesidade/epidemiologia , Glicemia/genética , Pressão Sanguínea/genética , Índice de Massa Corporal , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/genética , Doenças de Pequenos Vasos Cerebrais/epidemiologia , Doenças de Pequenos Vasos Cerebrais/genética , Transtornos Cerebrovasculares/genética , Humanos , Análise da Randomização Mendeliana , Obesidade/genética , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Relação Cintura-Quadril , Substância Branca/diagnóstico por imagem
17.
Hypertension ; 75(1): 71-78, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760884

RESUMO

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1ß (interleukin 1ß) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.


Assuntos
Pressão Sanguínea/genética , Hipertensão/etiologia , Adolescente , Alelos , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/genética , Masculino , Polimorfismo de Nucleotídeo Único
18.
Am J Physiol Heart Circ Physiol ; 318(2): H413-H424, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31886719

RESUMO

We previously showed that ARHGAP42 is a smooth muscle cell (SMC)-selective, RhoA-specific GTPase activating protein that regulates blood pressure and that a minor allele single nucleotide variation within a DNAse hypersensitive regulatory element in intron1 (Int1DHS) increased ARHGAP42 expression by promoting serum response factor binding. The goal of the current study was to identify additional transcriptional and posttranscriptional mechanisms that control ARHGAP42 expression. Using deletion/mutation, gel shift, and chromatin immunoprecipitation experiments, we showed that recombination signal binding protein for immunoglobulin κ-J region (RBPJ) and TEA domain family member 1 (TEAD1) binding to a conserved core region was required for full IntDHS transcriptional activity. Importantly, overexpression of the notch intracellular domain (NICD) or plating SMCs on recombinant jagged-1 increased IntDHS activity and endogenous ARHGAP42 expression while siRNA-mediated knockdown of TEAD1 inhibited ARHGAP42 mRNA levels. Re-chromatin immunoprecipitation experiments indicated that RBPJ and TEAD1 were bound to the Int1DHS enhancer at the same time, and coimmunoprecipitation assays indicated that these factors interacted physically. Our results also suggest TEAD1 and RBPJ bound cooperatively to the Int1DHS and that the presence of TEAD1 promoted the recruitment of NICD by RBPJ. Finally, we showed that ARHGAP42 expression was inhibited by micro-RNA 505 (miR505) which interacted with the ARHGAP42 3'-untranslated region (UTR) to facilitate its degradation and by AK124326, a long noncoding RNA that overlaps with the ARHGAP42 transcription start site on the opposite DNA strand. Since siRNA-mediated depletion of AK124326 was associated with increased H3K9 acetylation and RNA Pol-II binding at the ARHGAP42 gene, it is likely that AK124326 inhibits ARHGAP42 transcription.NEW & NOTEWORTHY First, RBPJ and TEAD1 converge at an intronic enhancer to regulate ARHGAP42 expression in SMCs. Second, TEAD1 and RBPJ interact physically and bind cooperatively to the ARHGAP42 enhancer. Third, miR505 interacts with the ARHGAP42 3'-UTR to facilitate its degradation. Finally, LncRNA, AK124326, inhibits ARHGAP42 transcription.


Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Proteínas Ativadoras de GTPase/genética , Regulação da Expressão Gênica/genética , Miócitos de Músculo Liso/metabolismo , Processamento de Proteína Pós-Traducional/genética , Regiões 3' não Traduzidas/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas Ativadoras de GTPase/biossíntese , Deleção de Genes , Técnicas de Silenciamento de Genes , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , MicroRNAs/genética , Mutação , Proteínas Nucleares/genética , RNA Longo não Codificante/genética , RNA Interferente Pequeno , Fatores de Transcrição/genética
19.
PLoS Genet ; 15(10): e1008405, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31647808

RESUMO

Obesity traits are causally implicated with risk of cardiometabolic diseases. It remains unclear whether there are similar causal effects of obesity traits on other non-communicable diseases. Also, it is largely unexplored whether there are any sex-specific differences in the causal effects of obesity traits on cardiometabolic diseases and other leading causes of death. We constructed sex-specific genetic risk scores (GRS) for three obesity traits; body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI, including 565, 324, and 337 genetic variants, respectively. These GRSs were then used as instrumental variables to assess associations between the obesity traits and leading causes of mortality in the UK Biobank using Mendelian randomization. We also investigated associations with potential mediators, including smoking, glycemic and blood pressure traits. Sex-differences were subsequently assessed by Cochran's Q-test (Phet). A Mendelian randomization analysis of 228,466 women and 195,041 men showed that obesity causes coronary artery disease, stroke (particularly ischemic), chronic obstructive pulmonary disease, lung cancer, type 2 and 1 diabetes mellitus, non-alcoholic fatty liver disease, chronic liver disease, and acute and chronic renal failure. Higher BMI led to higher risk of type 2 diabetes in women than in men (Phet = 1.4×10-5). Waist-hip-ratio led to a higher risk of chronic obstructive pulmonary disease (Phet = 3.7×10-6) and higher risk of chronic renal failure (Phet = 1.0×10-4) in men than women. Obesity traits have an etiological role in the majority of the leading global causes of death. Sex differences exist in the effects of obesity traits on risk of type 2 diabetes, chronic obstructive pulmonary disease, and renal failure, which may have downstream implications for public health.


Assuntos
Causas de Morte , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adiposidade/genética , Idoso , Pressão Sanguínea/genética , Índice de Massa Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neoplasias , Obesidade/complicações , Obesidade/mortalidade , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Risco , Acidente Vascular Cerebral , Relação Cintura-Quadril
20.
PLoS One ; 14(8): e0221248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430320

RESUMO

BACKGROUND: Systemic arterial hypertension (SAH) is a multifactorial condition that already affects one third of the worldwide population. The identification of candidate genes for hypertension is a challenge for the next years. Nevertheless, the small contribution of each individual genetic factor to the disease brings the necessity of evaluate genes in an integrative manner and taking into consideration the physiological interaction of functions. Angiotensin I-converting enzymes, ACE and ACE2, are key regulators of blood pressure that have counterbalance roles by acting on vasoactive peptides from Renin-Angiotensin-Aldosterone System (RAAS). Insertion/deletion (I/D) polymorphism of ACE gene and single nucleotide polymorphism G8790A of ACE2 gene have been associated with susceptibility to SAH, but the literature is controversial. We proposed to evaluate these two polymorphisms jointly exploring the combined effects of ACE and ACE2 genotypes on SAH susceptibility, an approach that have not been done yet for ACE and ACE2 polymorphisms. METHODS AND FINDINGS: This genetic association study included 117 hypertensive (mean age 59.7 years) patients and 123 normotensive and diabetes-free controls (mean age 57.5 years). ACE and ACE2 polymorphisms were genotyped by SYBR Green real-time PCR and RFLP-PCR, respectively. Crude and adjusted odds ratio (OR) values were calculated to estimate the susceptibility to SAH development. It was obtained homogeneity regarding distribution by sex, age range, smoking, alcohol consumption and body mass index (BMI) between case and control groups. No-association was verified for each gene individually, but the combination of ACE and ACE2 polymorphisms on female gender revealed a significative association for DD/G_ carriers who had a 3-fold increased risk to SAH development (p = 0.03), with a stronger susceptibility on DD/GG carriers (7-fold increased risk, p = 0.01). The D allele of ACE showed association with altered levels of lipid profile variables on case group (VLDL-cholesterol, p = 0.01) and DD genotype in all individuals analysis (triglycerides, p = 0.01 and VLDL-cholesterol, p = 0.01). CONCLUSION: These findings indicate that the combination of ACE and ACE2 polymorphisms effects may play a role in SAH predisposition been the DD/G_ genotype the susceptibility profile. This result allowed us to raise the hypothesis that an increased activity of ACE (prohypertensive effects) in conjunction with reduced ACE2 activity (antihypertensive effects) could be the underlining mechanism. The association of ACE D allele with lipid alterations indicate that this can be a marker of poor prognostic on SAH evolution and contribute to CVD development. Although these preliminary findings must be confirmed by further researches with larger sample size, we could observe that the integrative analysis of ACE and ACE2 can be an informative tool in hypertension understanding that needs to be explored in new studies.


Assuntos
Dislipidemias/epidemiologia , Predisposição Genética para Doença , Hipertensão/genética , Peptidil Dipeptidase A/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Pressão Sanguínea/genética , Brasil/epidemiologia , Estudos de Casos e Controles , Dislipidemias/genética , Feminino , Seguimentos , Frequência do Gene , Estudos de Associação Genética , Humanos , Hipertensão/epidemiologia , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores Sexuais , Adulto Jovem
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