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1.
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
2.
Am J Hum Genet ; 108(9): 1551-1557, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34329581

RESUMO

Clinical validity assessments of gene-disease associations underpin analysis and reporting in diagnostic genomics, and yet wide variability exists in practice, particularly in use of these assessments for virtual gene panel design and maintenance. Harmonization efforts are hampered by the lack of agreed terminology, agreed gene curation standards, and platforms that can be used to identify and resolve discrepancies at scale. We undertook a systematic comparison of the content of 80 virtual gene panels used in two healthcare systems by multiple diagnostic providers in the United Kingdom and Australia. The process was enabled by a shared curation platform, PanelApp, and resulted in the identification and review of 2,144 discordant gene ratings, demonstrating the utility of sharing structured gene-disease validity assessments and collaborative discordance resolution in establishing national and international consensus.


Assuntos
Consenso , Curadoria de Dados/normas , Doenças Genéticas Inatas/genética , Genômica/normas , Anotação de Sequência Molecular/normas , Austrália , Biomarcadores/metabolismo , Curadoria de Dados/métodos , Atenção à Saúde , Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Genômica/métodos , Humanos , Aplicativos Móveis/provisão & distribuição , Terminologia como Assunto , Reino Unido
3.
Hypertension ; 77(2): 284-295, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33390048

RESUMO

At the dawn of the new decade, it is judicious to reflect on the boom of knowledge about polygenic risk for essential hypertension supplied by the wealth of genome-wide association studies. Hypertension continues to account for significant cardiovascular morbidity and mortality, with increasing prevalence anticipated. Here, we overview recent advances in the use of big data to understand polygenic hypertension, as well as opportunities for future innovation to translate this windfall of knowledge into clinical benefit.


Assuntos
Predisposição Genética para Doença , Genômica , Hipertensão/genética , Estudo de Associação Genômica Ampla , Humanos , Anamnese
4.
Am J Med Genet C Semin Med Genet ; 187(1): 48-54, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33350578

RESUMO

More than 4,000 genes have been associated with recognizable Mendelian/monogenic diseases. When faced with a new diagnosis of a rare genetic disorder, health care providers increasingly turn to internet resources for information to understand the disease and direct care. Unfortunately, it can be challenging to find information concerning treatment for rare diseases as key details are scattered across a number of authoritative websites and numerous journal articles. The website and associated mobile device application described in this article begin to address this challenge by providing a convenient, readily available starting point to find treatment information. The site, Rx-genes.com (https://www.rx-genes.com/), is focused on those conditions where the treatment is directed against the mechanism of the disease and thereby alters the natural history of the disease. The website currently contains 633 disease entries that include references to disease information and treatment guidance, a brief summary of treatments, the inheritance pattern, a disease frequency (if known), nonmolecular confirmatory testing (if available), and a link to experimental treatments. Existing entries are continuously updated, and new entries are added as novel treatments appear in the literature.


Assuntos
Padrões de Herança , Doenças Raras , Pessoal de Saúde , Humanos , Internet
5.
Circulation ; 143(11): 1123-1138, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33334125

RESUMO

BACKGROUND: Although it has long been recognized that smooth muscle Na/K ATPase modulates vascular tone and blood pressure (BP), the role of its accessory protein phospholemman has not been characterized. The aim of this study was to test the hypothesis that phospholemman phosphorylation regulates vascular tone in vitro and that this mechanism plays an important role in modulation of vascular function and BP in experimental models in vivo and in humans. METHODS: In mouse studies, phospholemman knock-in mice (PLM3SA; phospholemman [FXYD1] in which the 3 phosphorylation sites on serines 63, 68, and 69 are mutated to alanines), in which phospholemman is rendered unphosphorylatable, were used to assess the role of phospholemman phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements. In vivo BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type and transgenic mice. In human studies, we searched human genomic databases for mutations in phospholemman in the region of the phosphorylation sites and performed analyses within 2 human data cohorts (UK Biobank and GoDARTS [Genetics of Diabetes Audit and Research in Tayside]) to assess the impact of an identified single nucleotide polymorphism on BP. This single nucleotide polymorphism was expressed in human embryonic kidney cells, and its effect on phospholemman phosphorylation was determined using Western blotting. RESULTS: Phospholemman phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of phospholemman phosphorylation in the PLM3SA mouse profoundly enhanced vascular responses to phenylephrine both in vitro and in vivo. In aging wild-type mice, phospholemman was hypophosphorylated, and this correlated with the development of aging-induced essential hypertension. In humans, we identified a nonsynonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in phospholemman. In human embryonic kidney cells, the R70C mutation prevented phospholemman phosphorylation at Ser68. This variant's rare allele is significantly associated with increased BP in middle-aged men. CONCLUSIONS: These studies demonstrate the importance of phospholemman phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for aging-induced essential hypertension in humans.

7.
J Public Health (Oxf) ; 42(3): 451-460, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32556213

RESUMO

BACKGROUND: We examined whether the greater severity of coronavirus disease 2019 (COVID-19) amongst men and Black, Asian and Minority Ethnic (BAME) individuals is explained by cardiometabolic, socio-economic or behavioural factors. METHODS: We studied 4510 UK Biobank participants tested for COVID-19 (positive, n = 1326). Multivariate logistic regression models including age, sex and ethnicity were used to test whether addition of (1) cardiometabolic factors [diabetes, hypertension, high cholesterol, prior myocardial infarction, smoking and body mass index (BMI)]; (2) 25(OH)-vitamin D; (3) poor diet; (4) Townsend deprivation score; (5) housing (home type, overcrowding) or (6) behavioural factors (sociability, risk taking) attenuated sex/ethnicity associations with COVID-19 status. RESULTS: There was over-representation of men and BAME ethnicities in the COVID-19 positive group. BAME individuals had, on average, poorer cardiometabolic profile, lower 25(OH)-vitamin D, greater material deprivation, and were more likely to live in larger households and in flats/apartments. Male sex, BAME ethnicity, higher BMI, higher Townsend deprivation score and household overcrowding were independently associated with significantly greater odds of COVID-19. The pattern of association was consistent for men and women; cardiometabolic, socio-demographic and behavioural factors did not attenuate sex/ethnicity associations. CONCLUSIONS: In this study, sex and ethnicity differential pattern of COVID-19 was not adequately explained by variations in cardiometabolic factors, 25(OH)-vitamin D levels or socio-economic factors. Factors which underlie ethnic differences in COVID-19 may not be easily captured, and so investigation of alternative biological and genetic susceptibilities as well as more comprehensive assessment of the complex economic, social and behavioural differences should be prioritised.


Assuntos
Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Infecções por Coronavirus/epidemiologia , Grupos Étnicos/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Grupos Minoritários/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Vigilância da População , Adulto , Idoso , Betacoronavirus , Índice de Massa Corporal , COVID-19 , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Fatores Socioeconômicos , Reino Unido/epidemiologia
8.
Nature ; 583(7814): 96-102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581362

RESUMO

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.


Assuntos
Internacionalidade , Programas Nacionais de Saúde , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Bases de Dados Factuais , Eritrócitos/metabolismo , Fator de Transcrição GATA1/genética , Humanos , Fenótipo , Locos de Características Quantitativas , Receptores de Trombopoetina/genética , Medicina Estatal , Reino Unido
9.
Nat Commun ; 11(1): 2542, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439900

RESUMO

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.


Assuntos
Arritmias Cardíacas/genética , Eletrocardiografia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Arritmias Cardíacas/fisiopatologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Endofenótipos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Locos de Características Quantitativas/genética
10.
Nat Commun ; 11(1): 1740, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269217

RESUMO

Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.


Assuntos
Núcleo Celular/genética , DNA Mitocondrial/genética , Herança Paterna/genética , Família , Feminino , Haplótipos/genética , Humanos , Masculino , Modelos Genéticos , Linhagem , Reprodutibilidade dos Testes
11.
Circulation ; 141(16): 1307-1317, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32148083

RESUMO

BACKGROUND: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. METHODS: We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. RESULTS: A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. CONCLUSIONS: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Pressão Sanguínea/genética , Loci Gênicos , Hipertensão , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Reino Unido
12.
Atherosclerosis ; 296: 11-17, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32005000

RESUMO

BACKGROUND AND AIMS: Recent studies have unveiled an association between ADAMTS7 gene variation and coronary artery disease (CAD) caused by atherosclerosis. We investigated if the ADAMTS7 Serine214-to-Proline substitution arising from a CAD-associated variant affected angiogenesis, since neovascularization plays an important role in atherosclerosis. METHODS AND RESULTS: ADAMTS7 knockdown in vascular endothelial cells (ECs) attenuated their angiogenesis potential, whereas augmented ADAMTS7-Ser214 expression had the opposite effect, leading to increased ECs migratory and tube formation ability. Proteomics analysis showed an increase in thrombospondin-1, a reported angiogenesis inhibitor, in culture media conditioned by ECs with ADAMTS7 knockdown and a decrease of thrombospondin-1 in media conditioned by ECs with ADAMTS7-Ser214 overexpression. Cleavage assay indicated that ADAMTS7 possessed thrombospondin-1 degrading activity, which was reduced by the Ser214-to-Pro substitution. The pro-angiogenic effect of ADAMTS7-Ser214 diminished in the presence of a thrombospondin-1 blocking antibody. CONCLUSIONS: The ADAMTS7 Ser217-to-Pro substitution as a result of ADAMTS7 polymorphism affects thrombospondin-1 degradation, thereby promoting atherogenesis through increased EC migration and tube formation.


Assuntos
Células Endoteliais/fisiologia , Neovascularização Fisiológica/genética , Polimorfismo de Nucleotídeo Único , Trombospondina 1/metabolismo , Proteína ADAMTS7/biossíntese , Proteína ADAMTS7/genética , Substituição de Aminoácidos , Movimento Celular , Meios de Cultivo Condicionados/farmacologia , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Placa Aterosclerótica/patologia , Proteômica , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes/metabolismo , Trombospondina 1/imunologia
13.
Hum Mol Genet ; 28(R2): R151-R161, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31411675

RESUMO

High blood pressure (BP) remains the major heritable and modifiable risk factor for cardiovascular disease. Persistent high BP, or hypertension, is a complex trait with both genetic and environmental interactions. Despite swift advances in genomics, translating new discoveries to further our understanding of the underlying molecular mechanisms remains a challenge. More than 500 loci implicated in the regulation of BP have been revealed by genome-wide association studies (GWAS) in 2018 alone, taking the total number of BP genetic loci to over 1000. Even with the large number of loci now associated to BP, the genetic variance explained by all loci together remains low (~5.7%). These genetic associations have elucidated mechanisms and pathways regulating BP, highlighting potential new therapeutic and drug repurposing targets. A large proportion of the BP loci were discovered and reported simultaneously by multiple research groups, creating a knowledge gap, where the reported loci to date have not been investigated in a harmonious way. Here, we review the BP-associated genetic variants reported across GWAS studies and investigate their potential impact on the biological systems using in silico enrichment analyses for pathways, tissues, gene ontology and genetic pleiotropy.


Assuntos
Pressão Sanguínea/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipertensão/genética , Animais , Ontologia Genética , Loci Gênicos , Pleiotropia Genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Software
14.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.


Assuntos
Cálcio/sangue , Doenças Cardiovasculares , Eletrocardiografia/métodos , Técnicas Eletrofisiológicas Cardíacas/métodos , Magnésio/sangue , Potássio/sangue , Doenças Assintomáticas/epidemiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Correlação de Dados , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
15.
Commun Biol ; 2: 119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937401

RESUMO

There is evidence that lower height is associated with a higher risk of coronary artery disease (CAD) and increased risk of type 2 diabetes (T2D). It is not clear though whether these associations are causal, direct or mediated by other factors. Here we show that one standard deviation higher genetically determined height (~6.5 cm) is causally associated with a 16% decrease in CAD risk (OR = 0.84, 95% CI 0.80-0.87). This causal association remains after performing sensitivity analyses relaxing pleiotropy assumptions. The causal effect of height on CAD risk is reduced by 1-3% after adjustment for potential mediators (lipids, blood pressure, glycaemic traits, body mass index, socio-economic status). In contrast, our data suggest that lung function (measured by forced expiratory volume [FEV1] and forced vital capacity [FVC]) is a mediator of the effect of height on CAD. We observe no direct causal effect of height on the risk of T2D.


Assuntos
Estatura/genética , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Pulmão/fisiologia , Análise da Randomização Mendeliana/métodos , Adulto , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Reino Unido/epidemiologia , Capacidade Vital
16.
Eur J Hum Genet ; 27(6): 952-962, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30679814

RESUMO

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.


Assuntos
Eletrocardiografia , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Países Baixos
17.
J Clin Hypertens (Greenwich) ; 20(10): 1473-1484, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30302936

RESUMO

Patients with grade 2-3 essential hypertension and postplacebo mean clinic systolic blood pressure (SBP) 160-190 mm Hg and 24-hour SBP 140-175 mm Hg by ambulatory blood pressure monitoring (ABPM) received 40 mg azilsartan medoxomil (AZL-M) monotherapy for 4 weeks. "Nonresponders" were then randomized to 8 weeks of double-blind treatment with AZL-M 40 mg, AZL-M/chlortalidone (CLD) 40/25, or AZL-M/CLD 40/12.5 mg. After 8 weeks, mean clinic SBP change was -21.1 (±1.04) mm Hg for AZL-M/CLD 40/25 mg, -15.8 (±1.08) mm Hg for AZL-M/CLD 40/12.5 mg, and -6.4 (±1.05) mm Hg for AZL-M 40 mg (P < 0.001 for both AZL-M/CLD vs AZL-M, ANCOVA). Drug discontinuation rates were 8.9% (AZL-M/CLD 40/25 mg), 7.5% (AZL-M 40 mg), and 3.9% (AZL-M/CLD 40/12.5 mg). Creatinine increased in 8.1% (AZL-M/CLD 40/25), 3.1% (AZL-M/CLD 40/12.5 mg), and 3.0% (AZL-M 40 mg) of patients. AZL-M/CLD was effective and well tolerated in patients not achieving blood pressure targets with AZL-M.


Assuntos
Benzimidazóis/uso terapêutico , Clortalidona/uso terapêutico , Quimioterapia Combinada/métodos , Hipertensão Essencial/tratamento farmacológico , Oxidiazóis/uso terapêutico , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial/métodos , Clortalidona/administração & dosagem , Clortalidona/efeitos adversos , Hipertensão Essencial/classificação , Hipertensão Essencial/epidemiologia , Hipertensão Essencial/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Oxidiazóis/administração & dosagem , Oxidiazóis/efeitos adversos , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Sístole
18.
N Engl J Med ; 379(15): 1403-1415, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30280646

RESUMO

BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Genoma Bacteriano , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológico , Sequenciamento Completo do Genoma , Antituberculosos/uso terapêutico , Etambutol/farmacologia , Genótipo , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Fenótipo , Pirazinamida/farmacologia , Rifampina/farmacologia , Tuberculose/microbiologia
19.
Ann Transl Med ; 6(15): 291, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30211179

RESUMO

Hypertension continues to be a major risk factor for global mortality, and recent genome-wide association studies (GWAS) have expanded in size, leading to the identification of further genetic loci influencing blood pressure. In light of the new knowledge from the largest cardiovascular GWAS to date, we review the potential impact of genomics on discovering potential drug targets, risk stratification with genetic risk scores, drug selection with pharmacogenetics, and exploring insights provided by gene-environment interactions.

20.
Lancet Diabetes Endocrinol ; 6(6): 464-475, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29655877

RESUMO

BACKGROUND: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. METHODS: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081. FINDINGS: Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001). INTERPRETATION: Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension. FUNDING: British Heart Foundation and UK National Institute for Health Research.


Assuntos
Anti-Hipertensivos/uso terapêutico , Bisoprolol/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Doxazossina/uso terapêutico , Hipertensão/tratamento farmacológico , Espironolactona/uso terapêutico , Aldosterona/metabolismo , Amilorida/uso terapêutico , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto
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