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1.
Zhen Ci Yan Jiu ; 46(8): 700-6, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472757

RESUMO

Acupuncture treatment can regulate blood pressure (BP) through multiple levels and ways. In the present paper, we reviewed the progress of researches on the underlying mechanisms of acupuncture in lowering BP from 1) regulation of activities of the neuroendocrine, 2) improvement of metabolic abnormality, and 3) alternation of gene expression in the heart and BP-regulation-related centers of the brain. The neuroendocrine mechanism mainly involves the inhibition of neuroinflammatory reaction in some higher brain regions, reduction of neuronal apoptosis, and suppression of the sympathetic cardiovascular regulatory functional areas of the brain stem, regulation of neurotransmitters and autonomic balance, activation of brain areas related to BP regulation, and promotion of functional connection between brain networks. The improvement of metabolic abnormality mainly refers to amelioration of imbalance of intestinal flora and target metabolites related to hypertension. The alteration of gene expression mainly manifests as up- and down-regulation of expression of genes related to oxidative stress, inflammation and vascular endothelial function in the myocardium, hypothalamus, rostral ventrolateral medulla. We reviewed the new research progress on the mechanism of acupuncture for hypertension, in order to provide evidence and research ideas for the treatment of related cardiovascular diseases by using acupuncture therapy in the future.


Assuntos
Terapia por Acupuntura , Hipertensão , Sistema Nervoso Autônomo , Pressão Sanguínea/genética , Humanos , Hipertensão/genética , Hipertensão/terapia , Bulbo
2.
Nat Genet ; 53(8): 1135-1142, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282336

RESUMO

Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome.


Assuntos
Peso ao Nascer/genética , Desenvolvimento Fetal/genética , Adulto , Glicemia/genética , Pressão Sanguínea/genética , Estatura/genética , Doenças Cardiovasculares/genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Islândia , Recém-Nascido , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
3.
Clin Pharmacol Ther ; 110(3): 723-732, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34231218

RESUMO

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (ß-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the ß-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10-8 ). rs139945292 was validated through BP response to ß-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10-4 , Beta = 3.09, diastolic BP response P = 5 × 10-3 , Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the ß-blocker treated patients' subgroup (P = 2.35 × 10-4 , odds ratio = 1.57, 95% confidence interval = 1.23-1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in ß-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in ß-blocker treated patients. Further investigation into this region is warranted.


Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Sistema Cardiovascular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Hipertensão/tratamento farmacológico , Afro-Americanos/genética , Idoso , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único/genética
4.
Nat Genet ; 53(8): 1260-1269, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34226706

RESUMO

Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total n ≈ 500,000) to impute exome-wide variants with accuracy R2 > 0.5 down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations (P < 5 × 10-8) involving 675 distinct rare protein-altering variants (MAF < 0.01) that passed stringent filters for likely causality. Across all traits, 49% of associations (578/1,189) occurred in genes with two or more hits; follow-up analyses of these genes identified allelic series containing up to 45 distinct 'likely-causal' variants. Our results demonstrate the utility of within-cohort imputation in population-scale genome-wide association studies, provide a catalog of likely-causal, large-effect coding variant associations and foreshadow the insights that will be revealed as genetic biobank studies continue to grow.


Assuntos
Bancos de Espécimes Biológicos , Frequência do Gene , Proteínas/genética , Sequenciamento Completo do Exoma/estatística & dados numéricos , Pressão Sanguínea/genética , Mapeamento Cromossômico/métodos , Mapeamento Cromossômico/estatística & dados numéricos , Marcadores Genéticos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Desequilíbrio de Ligação , Proteínas de Membrana/genética , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas/metabolismo , Receptores do Fator Natriurético Atrial/genética , Reino Unido , Sequenciamento Completo do Exoma/métodos
5.
Genes (Basel) ; 12(7)2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202464

RESUMO

ABO blood system is an inborn trait determined by the ABO gene. The genetic-phenotypic mechanism underneath the four mutually exclusive and collectively exhaustive types of O, A, B and AB could theoretically be elucidated. However, genetic polymorphisms in the human populations render the link elusive, and importantly, past studies using genetically determined rather than biochemically determined ABO types were not and could not be evaluated for the inference errors. Upon both blood-typing and genotyping a cohort of 1008 people of the Han Chinese population, we conducted a genome-wide association study in parallel with both binomial and multinomial log-linear models. Significant genetic variants are all mapped to the ABO gene, and are quantitatively evaluated for binary and multi-class classification performances. Three single nucleotide polymorphisms of rs8176719, rs635634 and rs7030248 would together be sufficient to establish a multinomial predictive model that achieves high accuracy (0.98) and F1 scores (micro 0.99 and macro 0.97). Using the set of identified ABO-associated genetic variants as instrumental variables, we demonstrate the application in causal analysis by Mendelian randomization (MR) studies on blood pressures (one-sample MR) and severe COVID-19 with respiratory failure (two-sample MR).


Assuntos
Sistema ABO de Grupos Sanguíneos/sangue , Sistema ABO de Grupos Sanguíneos/genética , COVID-19/genética , Polimorfismo de Nucleotídeo Único , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Pressão Sanguínea/genética , COVID-19/etiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Modelos Estatísticos , Testes Sorológicos
6.
Nat Commun ; 12(1): 3683, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140503

RESUMO

Blood pressure has a daily pattern, with higher values in the active period. Its elevation at the onset of the active period substantially increases the risk of fatal cardiovascular events. Renin secretion stimulated by renal sympathetic neurons is considered essential to this process; however, its regulatory mechanism remains largely unknown. Here, we show the importance of transient receptor potential melastatin-related 6 (TRPM6), a Mg2+-permeable cation channel, in augmenting renin secretion in the active period. TRPM6 expression is significantly reduced in the distal convoluted tubule of hypotensive Cnnm2-deficient mice. We generate kidney-specific Trpm6-deficient mice and observe a decrease in blood pressure and a disappearance of its circadian variation. Consistently, renin secretion is not augmented in the active period. Furthermore, renin secretion after pharmacological activation of ß-adrenoreceptor, the target of neuronal stimulation, is abrogated, and the receptor expression is decreased in renin-secreting cells. These results indicate crucial roles of TRPM6 in the circadian regulation of blood pressure.


Assuntos
Pressão Sanguínea/fisiologia , Túbulos Renais Distais/metabolismo , Rim/metabolismo , Renina/metabolismo , Canais de Cátion TRPM/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Pressão Sanguínea/genética , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Regulação para Baixo , Feminino , Regulação da Expressão Gênica/genética , Homeostase , Isoproterenol/farmacologia , Rim/patologia , Magnésio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Interferência de RNA , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Regulação para Cima
7.
Nat Genet ; 53(5): 630-637, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958779

RESUMO

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.


Assuntos
Predisposição Genética para Doença , Genômica , Hipertensão/genética , Rim/patologia , Processamento Alternativo/genética , Pressão Sanguínea/genética , Metilação de DNA/genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
8.
Blood Press ; 30(3): 196-204, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33792450

RESUMO

BACKGROUND AND AIMS: High blood pressure is the heritable risk factor for cardiovascular diseases. We investigated whether the presence of familial genetic and environmental risk factors are associated with increased risk of high blood pressure. METHODS: A total of 4,559 individuals from 401 families were included in this study. Familial aggregation analysis was carried out on systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and waist circumference (WC), and heritability was estimated for SBP and DBP. The association between familial risk factors and blood pressure traits including, incidence of hypertension, SBP and DBP was estimated separately using regression-based two-level Haseman-Elston (HE) method, with individual and familial BMI and WC as environmental exposures and familial genetic profile of known variants as genetic risk factors in 210 index families (≥2 hypertensive cases). Models were adjusted for the two nested sets of covariates. RESULTS: During a follow-up of 15 years, the SBP, DBP, BMI and WC were highly correlated in inter class of mother-offspring and intraclass of sister-sister with heritability of 30 and 25% for DBP and SBP, respectively. Among index families, those whose members with higher familial BMI or WC had significantly increased risk of hypertension and consistent, strong signals of rs2493134 (AGT) linked with SBP and DBP, rs976683 (NLGN1) linked with SBP and HTN, and epistasis of rs2021783 (TNXB) and known genetic variants linked with all blood pressure traits. CONCLUSIONS: Findings from this study show that familial genetic and environmental risk profile increase risk for high blood pressure beyond the effect of the individuals' own risk factors.


Assuntos
Pressão Sanguínea/genética , Índice de Massa Corporal , Exposição Ambiental/efeitos adversos , Variação Genética , Hipertensão , Modelos Cardiovasculares , Modelos Genéticos , Característica Quantitativa Herdável , Circunferência da Cintura , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Tenascina/genética , Tenascina/metabolismo
10.
BMC Genomics ; 22(1): 287, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879046

RESUMO

BACKGROUND: Alanine:glyoxylate aminotransferase 2 (AGXT2; EC 2.6.1.44) is the only enzyme that degrades the R-form of 3-aminoisobutyrate, an intermediate metabolite of thymine. AGXT2, as well as diaminoarginine dimethylaminohydrolase 1 (DDAH1; EC 3.5.3.18), works as an enzyme that degrades asymmetric dimethylarginine (ADMA), which competitively inhibits the nitric oxide synthase family. Thus, these two enzyme activities may change vascular vulnerability for a lifetime via the nitric oxide (NO) system. We investigated the association between vascular conditions and diseases such as hypertension and diabetes mellitus and polymorphisms of these two genes in 750 older Japanese subjects (mean age ± standard deviation, 77.0 ± 7.6 years) recruited using the complete enumeration survey method in the Nakayama study. Demographic and biochemical data, such as blood pressure (BP) and casual blood sugar (CBS), were obtained. Four functional single nucleotide polymorphisms (SNPs; rs37370, rs37369, rs180749, and rs16899974) of AGXT2 and one functional insertion/deletion polymorphism in the promotor region with four SNPs (rs307894, rs669173, rs997251, and rs13373844) of DDAH1 were investigated. Plasma ADMA was also analyzed in 163 subjects. RESULTS: The results of multiple regression analysis showed that a loss of the functional haplotype of AGXT2, CAAA, was significantly positively correlated with BP (systolic BP, p = 0.034; diastolic BP, p = 0.025) and CBS (p = 0.021). No correlation was observed between DDAH1 and either BP or CBS. ADMA concentrations were significantly elevated in subjects with two CAAA haplotypes compared with subjects without the CAAA haplotype (p = 0.033). CONCLUSIONS: Missense variants of AGXT2, but not DDAH1, may be related to vulnerability to vascular diseases such as hypertension and DM via the NO system.


Assuntos
Glicemia , Pressão Sanguínea , Polimorfismo de Nucleotídeo Único , Transaminases/genética , Amidoidrolases/genética , Arginina , Pressão Sanguínea/genética , Humanos , Japão , Inquéritos e Questionários
11.
Medicine (Baltimore) ; 100(15): e25530, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847678

RESUMO

OBJECTIVE: The present study aimed to conduct a systematic review and meta-analysis to evaluate the relationships between ATP2B1 gene polymorphisms with blood pressure (BP) level and susceptibility to hypertension. METHODS: PubMed, Web of Science, Embase and China National Knowledge Infrastructure (CNKI) Databases were systematically searched by 2 independent researchers to screen studies on ATP2B1 gene polymorphisms and BP related phenotypes. The records retrieval period was limited from the formation of the database to March 4, 2021. Pooled odds rations (ORs) or ß and their 95% confidence intervals (95%CI) were calculated to assess the association between ATP2B1 gene polymorphisms and the risk of hypertension or BP levels. Publication bias and sensitivity analysis were conducted to find potential bias. All the statistical analysis were conducted with Stata version 11.0 software. RESULTS: A total of 15 articles were ultimately included in the present study, including 15 polymorphisms of ATP2B1 gene. Nine articles (N = 65,362) reported the polymorphism rs17249754, and 7 articles(N = 91,997) reported rs2681472 (both loci were reported in 1 article). Meta-analysis showed that rs17249754 (G/A) and rs2681472 (A/G) were associated with the susceptibility to hypertension (rs17249754: OR = 1.19, 95%CI: 1.10-1.28; rs2681472: OR = 1.15, 95%CI: 1.12-1.17), and were positively associated with systolic BP (SBP) and diastolic blood pressure (DBP) (rs17249754: SBP, ß=1.01, 95%CI: 0.86-1.16, DBP, ß=0.48, 95%CI: 0.30-0.66; rs2681472: SBP, ß=0.92, 95%CI: 0.77-1.07, DBP, ß=0.50, 95%CI: 0.42-0.58) in the additive genetic model. Subgroup analysis stratified by race, population, sample size, and BP measurement method revealed that the association between A allele in rs2681472 polymorphism and risk of hypertension was slightly stronger in European (EUR) populations (OR = 1.16, 95%CI: 1.13-1.20) than in East Asians (OR = 1.14, 95%CI: 1.10-1.17). While in East Asians, relation between rs17249754 with risk of hypertension (OR = 1.19, 95%CI: 1.10-1.28) is stronger than rs2681472 (OR = 1.14, 95%CI: 1.10-1.17). CONCLUSIONS: Our study demonstrated that ATP2B1 gene polymorphism rs2681472 and rs17249754 were associated with BP levels and the susceptibility to hypertension.


Assuntos
Pressão Sanguínea/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo Genético/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo
12.
Mol Biol Rep ; 48(3): 2553-2560, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33759050

RESUMO

MicroRNAs are important in development of disease, and description of novel microRNAs adds to the pool of microRNAs that can be targeted for diagnostic and therapeutic purposes in disease. Herein, we aimed to describe novel microRNAs in a normotensive and hypertensive African population and relate their expression to blood pressure parameters and hypertension status. Previous work using next-generation sequencing showed differential expression of two novel microRNAs in the blood of normotensives and hypertensives. Herein, we have investigated these novel microRNAs by quantitative reverse transcription polymerase chain reaction in a cohort of 881 participants in this study. The relationship between the novel microRNAs and systolic and diastolic blood pressure as well as mean arterial pressure was also investigated. Age and sex-adjusted Spearman's correlations were used to assess the relationship between microRNAs and cardiovascular risk profile variables whilst multivariable logistic regression models were used to assess the association of microRNAs with screen-detected and known hypertension. The novel microRNAs (miR-novel-chr1_36178 and miR-novel-chr15_18383) were significantly dysregulated by hypertension status. The expression of miR-novel-chr1_36178 differed according to sex, correlated with mean arterial pressure and systolic and diastolic blood pressure at higher levels of expression and was associated with screen-detected hypertension. The association of miR-novel-chr1_36178 expression with mean arterial pressure and systolic and diastolic blood pressure, as well as its dysregulation according to hypertension status suggests its possible utility as a biomarker target for hypertension diagnosis and/or therapeutics. Furthermore, its association with screen detected hypertension and dose-response relationship with blood pressure suggests it may be used to identify and monitor individuals at risk of hypertension.


Assuntos
Pressão Sanguínea/genética , MicroRNAs/genética , População Urbana , Adulto , Feminino , Regulação da Expressão Gênica , Humanos , Modelos Lineares , Masculino , MicroRNAs/metabolismo , Razão de Chances , África do Sul , Estatísticas não Paramétricas
13.
Biol Psychiatry ; 89(8): 817-824, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33766239

RESUMO

BACKGROUND: Findings from randomized controlled trials have yielded conflicting results on the association between blood pressure (BP) and dementia traits. We tested the hypothesis that a causal relationship exists between systolic BP (SBP) and/or diastolic BP (DBP) and risk of Alzheimer's disease (AD). METHODS: We performed a generalized summary Mendelian randomization (GSMR) analysis using summary statistics of a genome-wide association study meta-analysis of 299,024 individuals of SBP or DBP as exposure variables against three different outcomes: 1) AD diagnosis (International Genomics of Alzheimer's Project), 2) maternal family history of AD (UK Biobank), and 3) paternal family history of AD (UK Biobank). Finally, a combined meta-analysis of 368,440 individuals that included these three summary statistics was used as final outcome. RESULTS: GSMR applied to the International Genomics of Alzheimer's Project dataset revealed a significant effect of high SBP lowering the risk of AD (ßGSMR = -0.19, p = .04). GSMR applied to the maternal family history of AD UK Biobank dataset (SBP [ßGSMR = -0.12, p = .02], DBP [ßGSMR = -0.10, p = .05]) and to the paternal family history of AD UK Biobank dataset (SBP [ßGSMR = -0.16, p = .02], DBP [ßGSMR = -0.24, p = 7.4 × 10-4]) showed the same effect. A subsequent combined meta-analysis confirmed the overall significant effect for the other SBP analyses (ßGSMR = -0.14, p = .03). The DBP analysis in the combined meta-analysis also confirmed a DBP effect on AD (ßGSMR = -0.14, p = .03). CONCLUSIONS: A causal effect exists between high BP and a reduced late-life risk of AD. The results were obtained through careful consideration of confounding factors and the application of complementary MR methods on independent cohorts.


Assuntos
Hipertensão , Análise da Randomização Mendeliana , Bancos de Espécimes Biológicos , Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Humanos , Reino Unido/epidemiologia
14.
Alzheimers Res Ther ; 13(1): 41, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563324

RESUMO

BACKGROUND: Observational studies suggest that the use of antihypertensive medications (AHMs) is associated with a reduced risk of Alzheimer's disease (AD); however, these findings may be biased by confounding and reverse causality. We aimed to explore the effects of blood pressure (BP) and lowering systolic BP (SBP) via the protein targets of different AHMs on AD through a two-sample Mendelian randomization (MR) approach. METHODS: Genetic proxies from genome-wide association studies of BP traits and BP-lowering variants in genes encoding AHM targets were extracted. Estimates were calculated by inverse-variance weighted method as the main model. MR Egger regression and leave-one-out analysis were performed to identify potential violations. RESULTS: There was limited evidence that genetically predicted SBP/diastolic BP level affected AD risk based on 400/398 single nucleotide polymorphisms (SNPs), respectively (all P > 0.05). Suitable genetic variants for ß-blockers (1 SNP), angiotensin receptor blockers (1 SNP), calcium channel blockers (CCBs, 45 SNPs), and thiazide diuretics (5 SNPs) were identified. Genetic proxies for CCB [odds ratio (OR) = 0.959, 95% confidence interval (CI) = 0.941-0.977, P = 3.92 × 10-6] and overall use of AHMs (OR = 0.961, 95% CI = 0.944-0.978, P = 5.74 × 10-6, SNPs = 52) were associated with a lower risk of AD. No notable heterogeneity and directional pleiotropy were identified (all P > 0.05). Additional analyses partly support these results. No single SNP was driving the observed effects. CONCLUSIONS: This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.


Assuntos
Doença de Alzheimer , Anti-Hipertensivos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética
15.
BMC Cardiovasc Disord ; 21(1): 73, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541272

RESUMO

BACKGROUND: There is an individual variation in response to antihypertensive effect of the angiotensin II receptor antagonist. This study aimed to determine the allele and genotype frequencies of CYP2C9 and AGTR1 genetic polymorphisms and explore the potential role of these polymorphisms in guiding the selection of angiotensinIIreceptor antagonist in Han Chinese hypertensive patients. METHODS: Totally 2419 Han Chinese hypertensive patients and 126 normotensive controls were recruited in this study. Venous blood samples were collected from each patient, and the genetic polymorphisms of CYP2C9 and AGTR1 were assessed using a gene chip platform. The allele and genotype frequency of each gene and the combined genotypes in this study were analyzed respectively. RESULTS: The gene chip analysis identified an allelic frequency of 96.51% for CYP2C9*1 and 3.49% for CYP2C9*3 in the cohort of Han Chinese hypertensive patients. Statistical analysis showed that the frequency of wild-type homozygous for CYP2C9*1/*1 was 93.30%, while the frequency of heterozygous for *1/*3 or mutant homozygous for *3/*3 was 6.41% or 0.29%. Meanwhile, we detected allelic frequencies of 95.06% and 4.94% for the A and C allele of AGTR1, respectively. While the genotype frequency of wild-type homozygous for AA was 90.41%, the frequency of heterozygous for AC or mutant homozygous for CC was 9.30% or 0.29%. Notably, we observed that 84.66% (2048/2419) of the subjects exhibited a combined genotype of CYP2C9 and AGTR1 as *1/*1 + AA, while the combined genotypes *3/*3 + AC or *3/*3 + CC were not detected in hypertension patients. Besides, no significant association was found between normotensive controls and hypertensive patients, or among the three grades of hypertensive patients. CONCLUSIONS: These data revealed the polymorphisms characteristics of CYP2C9 and AGTR1 in Han Chinese hypertensive patients, providing valuable information for genotype-based antihypertension therapy in prospective clinical studies in the future.


Assuntos
Pressão Sanguínea/genética , Citocromo P-450 CYP2C9/genética , Hipertensão/genética , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , China/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hipertensão/diagnóstico , Hipertensão/etnologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença
16.
Internist (Berl) ; 62(3): 223-235, 2021 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-33595671

RESUMO

A genetic influence on blood pressure was demonstrated more than 100 years ago and a simple Mendelian inheritance was initially presumed. Platt and Pickering conducted a lively debate on this topic. Platt favored the idea that a single gene or only a few genes were responsible for high blood pressure. Pickering presented research results, which supported the assumption that many genes exerted an influence on blood pressure. This was all in a period when it was not even known what genes were. Genome-wide association studies (GWAS) according to the Pickering model have identified > 500 blood pressure relevant gene loci, which are distributed over the whole genome. Each individual gene exerts only a small effect on blood pressure. The dark horses of hypertension research are the secondary causes. In pheochromocytoma, primary aldosteronism, Cushing's syndrome and even fibromuscular dysplasia (renovascular hypertension) the results indicate that a genetic cause regularly underlies secondary hypertension. This would therefore also partially confirm Platt's theory. In the meantime, a multitude of forms of hypertension have been described with a genetic inheritance according to Mendel. Each of these genetic variants exerts a considerable influence on blood pressure. A multitude of novel physiological mechanisms were explained by this. These findings will become therapeutically important. Therefore, it is incumbent upon clinicians to be optimally informed about these research results.


Assuntos
Pressão Sanguínea , Hipertensão , Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único
17.
Hypertension ; 77(2): 376-382, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33390040

RESUMO

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11-1.22]; P=1×10-11; diastolic blood pressure: OR, 1.25 [95% CI, 1.16-1.35]; P=3×10-8; pulse pressure: OR, 1.1 [95% CI, 1.0-1.2]; P=0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57-0.76]; P=8×10-9) and ß-blockers (OR, 0.61 [95% CI, 0.46-0.81]; P=6×10-4) decreased the risk of AF. Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or ß-blockade could reduce the risk of AF.


Assuntos
Fibrilação Atrial/genética , Pressão Sanguínea/genética , Hipertensão/genética , Anti-Hipertensivos/uso terapêutico , Bancos de Espécimes Biológicos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/tratamento farmacológico , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Reino Unido
18.
Hypertension ; 77(2): 367-375, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33390054

RESUMO

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25-1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15-1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24-1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14-1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24-1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12-1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.


Assuntos
Pressão Sanguínea/genética , Doenças Cardiovasculares/epidemiologia , Hipertensão/epidemiologia , Idoso , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/genética , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertensão/genética , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco , Reino Unido/epidemiologia
19.
Hypertension ; 77(2): 582-593, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33390052

RESUMO

Genome-wide association studies have found a number of potential genes involved in blood pressure regulation; however, the functional role of many of these candidates has yet to be established. One such candidate gene is CLCN6, which encodes the transmembrane protein, chloride channel 6 (ClC-6). Although the CLCN6 locus has been widely associated with human blood pressure regulation, the mechanistic role of ClC-6 in blood pressure homeostasis at the molecular, cellular, and physiological levels is completely unknown. In this study, we demonstrate that rats with a functional knockout of ClC-6 on the Dahl Salt-Sensitive rat background (SS-Clcn6) have lower diastolic but not systolic blood pressures. The effect of diastolic blood pressure attenuation was independent of dietary salt exposure in knockout animals. Moreover, SS-Clcn6 rats are protected from hypertension-induced cardiac hypertrophy and arterial stiffening; however, they have impaired vasodilation and dysregulated intracellular calcium handling. ClC-6 is highly expressed in vascular smooth muscle cells where it is targeted to the Golgi apparatus. Using bilayer electrophysiology, we provide evidence that recombinant human ClC-6 protein can function as a channel. Last, we demonstrate that loss of ClC-6 function reduces Golgi calcium stores, which may play a previously unidentified role in vascular contraction and relaxation signaling in vascular smooth muscle cells. Collectively, these data indicate that ClC-6 may modulate blood pressure by regulating Golgi calcium reserves, which in turn contribute to vascular smooth muscle function.


Assuntos
Cálcio/metabolismo , Canais de Cloreto/metabolismo , Complexo de Golgi/metabolismo , Contração Muscular/genética , Músculo Liso Vascular/fisiologia , Rigidez Vascular/genética , Animais , Pressão Sanguínea/genética , Canais de Cloreto/genética , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Endogâmicos Dahl , Sódio na Dieta
20.
Nat Genet ; 53(2): 135-142, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33495597

RESUMO

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.


Assuntos
Cardiomiopatia Hipertrófica/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Pressão Sanguínea/genética , Miosinas Cardíacas/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Forminas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Fatores de Risco , Sarcômeros/genética , Adulto Jovem
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