RESUMEN
RATIONALE: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. OBJECTIVE: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. METHODS AND RESULTS: As in dopamine ß-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine ß-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine ß-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine. CONCLUSIONS: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.
Asunto(s)
Codón sin Sentido , Grupo Citocromo b/genética , Hipotensión Ortostática/genética , Glándulas Suprarrenales/metabolismo , Adulto , Animales , Ácido Ascórbico/metabolismo , Encéfalo/metabolismo , Catecolaminas/metabolismo , Femenino , Humanos , Hipotensión Ortostática/patología , Ratones , Ratones Endogámicos C57BL , Norepinefrina/metabolismo , Linaje , Vesículas Secretoras/metabolismo , SíndromeRESUMEN
The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
Asunto(s)
Arritmias Cardíacas/genética , Síndrome de Brugada/genética , Electrocardiografía , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas Adaptadoras Transductoras de Señales/genética , Arritmias Cardíacas/fisiopatología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Síndrome de Brugada/fisiopatología , Trastorno del Sistema de Conducción Cardíaco , Muerte Súbita Cardíaca/patología , Femenino , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Masculino , Canal de Sodio Activado por Voltaje NAV1.5/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Represoras/genética , Canales de Potasio Shab/genética , Canales de Potasio Shal/genéticaRESUMEN
Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
Asunto(s)
Eritrocitos/metabolismo , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Fenotipo , Animales , Ciclo Celular/genética , Citocinas/metabolismo , Drosophila melanogaster/genética , Eritrocitos/citología , Femenino , Regulación de la Expresión Génica/genética , Hematopoyesis/genética , Hemoglobinas/genética , Humanos , Masculino , Ratones , Especificidad de Órganos , Polimorfismo de Nucleótido Simple/genética , Interferencia de ARN , Transducción de Señal/genéticaRESUMEN
Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
Asunto(s)
Presión Sanguínea , Diástole , Genética de Población , Sístole , Población Blanca/genética , Presión Arterial , Biología Computacional/métodos , Europa (Continente) , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple , Control de Calidad , Sitios de Carácter Cuantitativo , Factores de RiesgoRESUMEN
Vitamin D deficiency is one of the most common nutritional deficiencies worldwide. Maternal vitamin D deficiency is associated with increased susceptibility to hypertension in offspring, but the reasons for this remain unknown. The aim of this study was to determine if parental vitamin D deficiency leads to altered DNA methylation in offspring that may relate to hypertension. Male and female Sprague-Dawley rats were fed a standard or vitamin D-depleted diet. After 10 wk, nonsibling rats were mated. The conceived pups received standard chow. We observed an increased systolic and diastolic blood pressure in the offspring from depleted parents (F1-depl). Genome-wide methylation analyses in offspring identified hypermethylation of the promoter region of the Pannexin-1 (Panx1) gene in F1-depl rats. Panx1 encodes a hemichannel known to be involved in endothelial-dependent relaxation, and we demonstrated that in F1-depl rats the increase in blood pressure was associated with impaired endothelial relaxation of the large vessels, suggesting an underlying biological mechanism of increased blood pressure in children from parents with vitamin deficiency. Parental vitamin D deficiency is associated with epigenetic changes and increased blood pressure levels in offspring.
Asunto(s)
Presión Sanguínea/genética , Conexinas/genética , Metilación de ADN , Hipertensión/genética , Proteínas del Tejido Nervioso/genética , Exposición Paterna , Complicaciones del Embarazo/genética , Efectos Tardíos de la Exposición Prenatal/genética , Deficiencia de Vitamina D/genética , Animales , Factor Natriurético Atrial/genética , Western Blotting , Endotelio Vascular/fisiopatología , Epigénesis Genética , Femenino , Hipertensión/fisiopatología , Masculino , Exposición Materna , Hormona Paratiroidea/metabolismo , Embarazo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Angiotensina Tipo 1/genética , Receptores de Calcitriol/genética , Renina/genética , Vasodilatación/genética , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Deficiencia de Vitamina D/metabolismoRESUMEN
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped â¼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in â¼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
Asunto(s)
Presión Sanguínea/genética , Enfermedades Cardiovasculares/genética , Mapeo Cromosómico , Estudio de Asociación del Genoma Completo , Adulto , Anciano , Enfermedades Cardiovasculares/fisiopatología , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
Asunto(s)
Estudio de Asociación del Genoma Completo , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Factores Sexuales , Femenino , Frecuencia de los Genes , Humanos , Masculino , Razón de Masculinidad , Sexismo , Población Blanca/genéticaRESUMEN
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain â¼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum Nâ=â32,225). We collected 8 further cohorts (Nâ=â17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Asunto(s)
Cadherinas/genética , Colesterol/genética , Cromosomas Humanos Par 4/genética , Lípidos/sangre , Lípidos/genética , Relación Cintura-Cadera , Tejido Adiposo/metabolismo , Distribución de la Grasa Corporal , Colesterol/sangre , Mapeo Cromosómico , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Lipoproteínas/sangre , Lipoproteínas/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Protocadherinas , Sitios de Carácter Cuantitativo/genética , Factores de Riesgo , Triglicéridos/sangre , Triglicéridos/genética , Población Blanca/genéticaRESUMEN
The ichneumonid wasp Venturia canescens (Hymenoptera) has been studied extensively for foraging behaviour and population dynamics of sexually (arrhenotokous) and parthenogenetically (thelytokous) reproducing individuals. Here we report the development of a set of microsatellite markers for V.canescens and use them to show that arrhenotokous individuals have more genetic variability than thelytokous ones, which are even homozygous for all tested loci. Crosses between arrhenotokous individuals suggested one marker, Vcan071, to be linked with the Complementary Sex Determiner (CSD) locus and one, Vcan109, with the Virus Like Protein (vlp-p40) locus. The genome size of V. canescens was estimated to be 274-279 Mb. We discuss how both reproductive modes can give rise to the observed genetic variability and how the new markers can be used for future genetic studies of V. canescens.
Asunto(s)
Variación Genética , Genoma de los Insectos/genética , Repeticiones de Microsatélite/genética , Avispas/genética , Animales , Cruzamientos Genéticos , ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones/genética , Femenino , Tamaño del Genoma/genética , Haplotipos , Masculino , Partenogénesis/genética , Filogenia , Reproducción/genética , Avispas/clasificaciónRESUMEN
Epigenetics studies inheritable changes of genes and gene expression that do not concern DNA nucleotide variation. Such modifications include DNA methylation, several forms of histone modification, and microRNAs. From recent studies, we know not only that genetic changes account for heritable phenotypic variation, but that epigenetic changes also play an important role in the variation of predisposition to disease and to drug response. In this review, we discuss recent evidence of epigenetic changes that play an important role in the development of cardiac hypertrophy and heart failure and may dictate response to therapy.
Asunto(s)
Epigénesis Genética , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/genética , Farmacogenética , Metilación de ADN , Humanos , MicroARNs/genéticaRESUMEN
We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.
Asunto(s)
Presión Sanguínea/genética , Islas de CpG/genética , Metilación de ADN , Epigenoma/genética , Hipertensión Esencial/genética , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Adolescente , Adulto , Anciano , Población Negra/estadística & datos numéricos , Índice de Masa Corporal , Estudios de Cohortes , Enfermedades en Gemelos/epidemiología , Enfermedades en Gemelos/genética , Hipertensión Esencial/epidemiología , Hipertensión Esencial/etnología , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Estudios en Gemelos como Asunto , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND: Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). METHODS: CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. RESULTS: I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28±4% vs. 35±6%, p = 0.02; sham 45±6% vs. 43±4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. CONCLUSION: Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Receptores de Interleucina-6/antagonistas & inhibidores , Remodelación Ventricular/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Fibrosis/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiopatología , Hemodinámica/efectos de los fármacos , Hipertrofia/metabolismo , Interleucina-6/sangre , Interleucina-6/metabolismo , Masculino , Ratones Endogámicos C57BL , Microscopía Fluorescente , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Receptores de Interleucina-6/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
Asunto(s)
Cardiomegalia/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Animales , HumanosRESUMEN
BACKGROUND: Telomere length has been associated with coronary artery disease and heart failure. We studied whether leukocyte telomere length is associated with left ventricular ejection fraction (LVEF) after ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Leukocyte telomere length (LTL) was determined using the monochrome multiplex quantitative PCR method in 353 patients participating in the glycometabolic intervention as adjunct to primary percutaneous coronary intervention in STEMI III trial. LVEF was assessed by magnetic resonance imaging. The mean age of patients was 58.9 ± 11.6 years, 75 % were male. In age- and gender-adjusted models, LTL at baseline was significantly associated with age (beta ± standard error; -0.33 ± 0.01; P < 0.01), gender (0.15 ± 0.03; P < 0.01), TIMI flow pre-PCI (0.05 ± 0.03; P < 0.01), TIMI flow post-PCI (0.03 ± 0.04; P < 0.01), myocardial blush grade (-0.05 ± 0.07; P < 0.01), serum glucose levels (-0.11 ± 0.01; P = 0.03), and total leukocyte count (-0.11 ± 0.01; P = 0.04). At 4 months after STEMI, LVEF was well preserved (54.1 ± 8.4 %) and was not associated with baseline LTL (P = 0.95). Baseline LTL was associated with n-terminal pro-brain natriuretic peptide (NT-proBNP) at 4 months (-0.14 ± 0.01; P = 0.02), albeit not independent for age and gender. CONCLUSION: Our study does not support a role for LTL as a causal factor related to left ventricular ejection fraction after STEMI.
Asunto(s)
Infarto del Miocardio/epidemiología , Infarto del Miocardio/genética , Acortamiento del Telómero/genética , Disfunción Ventricular Izquierda/epidemiología , Disfunción Ventricular Izquierda/genética , Enfermedad Aguda , Causalidad , Terapia Combinada , Comorbilidad , Método Doble Ciego , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Hipoglucemiantes/uso terapéutico , Incidencia , Leucocitos , Estudios Longitudinales , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Infarto del Miocardio/terapia , Países Bajos/epidemiología , Intervención Coronaria Percutánea/estadística & datos numéricos , Efecto Placebo , Medición de Riesgo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/terapiaRESUMEN
AIMS: Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart failure and whether this association is superior to chronological age as defined by date of birth. METHODS AND RESULTS: We measured leucocyte telomere length in 3275 patients with chronic ischaemic systolic heart failure participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) study. The primary composite endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, which occurred in 575 patients during follow-up. We observed a significant association of leucocyte telomere lengths with the primary endpoint (hazard ratio 1.10; 95% confidence interval 1.01-1.20; P=0.03). However, this observation was not superior to age as defined by date of birth. The neutral effect of rosuvastatin treatment on clinical outcomes was not modified by baseline telomere length. CONCLUSION: Biological age as defined by leucocyte telomere length was associated with clinical outcomes in patients with ischaemic heart failure, but this association did not add prognostic information above age as defined by date of birth.
Asunto(s)
Insuficiencia Cardíaca/diagnóstico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Isquemia Miocárdica/genética , Rosuvastatina Cálcica/uso terapéutico , Telómero , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Biomarcadores , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Leucocitos/fisiología , Masculino , Isquemia Miocárdica/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVE: Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations (n=20â242). DESIGN AND METHODS: The study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13â363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. RESULTS: In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). CONCLUSION: In conclusion, our findings in 20â242 individuals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.
Asunto(s)
Alanina Transaminasa/metabolismo , Consumo de Bebidas Alcohólicas/metabolismo , Interacción Gen-Ambiente , Canales Iónicos/genética , Hepatopatías/genética , Proteínas Mitocondriales/genética , Obesidad/metabolismo , gamma-Glutamiltransferasa/metabolismo , Adulto , Estudios de Cohortes , Femenino , Finlandia , Humanos , Hepatopatías/metabolismo , Pruebas de Función Hepática , Modelos Logísticos , Masculino , Persona de Mediana Edad , Países Bajos , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Proteína Desacopladora 2RESUMEN
Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (ßLDL-C=0.135, ßTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Colesterol/sangre , Mutación Missense/genética , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Países BajosRESUMEN
BACKGROUND: The PR interval on the ECG reflects atrial depolarization and atrioventricular nodal delay which can be partially differentiated by P wave duration and PR segment, respectively. Genome-wide association studies have identified several genetic loci for PR interval, but it remains to be determined whether this is driven by P wave duration, PR segment, or both. METHODS AND RESULTS: We replicated 7 of the 9 known PR interval loci in 16 468 individuals of European ancestry. Four loci were unambiguously associated with PR segment, while the others were shared for P wave duration and PR segment. Next, we performed a genome-wide analysis on P wave duration and PR segment separately and identified 5 novel loci. Single-nucleotide polymorphisms in KCND3 (P=8.3×10(-11)) and FADS2 (P=2.7×10(-8)) were associated with P wave duration, whereas single-nucleotide polymorphisms near IL17D (P=2.3×10(-8)), in EFHA1 (P=3.3×10(-10)), and in LRCH1 (P=2.1×10(-8)) were associated with PR segment. Analysis on DNA elements indicated that genome-wide significant single-nucleotide polymorphisms were enriched at genomic regions suggesting active gene transcription in the human right atrium. Quantitative polymerase chain reaction showed that genes were significantly higher expressed in the right atrium and atrioventricular node compared with left ventricle (P=5.6×10(-6)). CONCLUSIONS: Genetic associations of PR interval seem to be mainly driven by genetic determinants of the PR segment. Some of the PR interval associations are strengthened by a directional consistent effect of genetic determinants of P wave duration. Through genome-wide association we also identified genetic variants specifically associated with P wave duration which might be relevant for cardiac biology.
Asunto(s)
Estudio de Asociación del Genoma Completo , Fallo Renal Crónico/genética , Nodo Atrioventricular/metabolismo , Proteínas de Unión al Calcio/genética , Estudios de Cohortes , Electrocardiografía , Ácido Graso Desaturasas/genética , Regulación de la Expresión Génica , Sitios Genéticos , Genotipo , Atrios Cardíacos/metabolismo , Ventrículos Cardíacos/metabolismo , Humanos , Interleucina-17/genética , Fallo Renal Crónico/patología , Proteínas de Microfilamentos/genética , Polimorfismo de Nucleótido Simple , Canales de Potasio Shal/genéticaRESUMEN
Endothelin-1 (ET-1) and adrenomedullin (ADM) are circulating vasoactive peptides involved in vascular homeostasis and endothelial function. Elevated levels of plasma ET-1 and ADM, and their biologically stable surrogates, C-terminal-pro-endothelin-1 (CT-pro-ET-1) and midregional proadrenomedullin (MR-pro-ADM), are predictors of cardiac death and heart failure. We studied the association of common genetic variation with MR-pro-ADM and CT-pro-ET-1 by genome-wide association analyses in 3444 participants of European ancestry. We performed follow-up genotyping of single nucleotide polymorphisms (SNPs) that showed suggestive or significant association in the discovery stage in additional 3230 participants. The minor variants in KLKB1 (rs4253238) and F12 (rs2731672), both part of the kallikrein-kinin system, were associated with higher MR-pro-ADM (P=4.46E-52 and P=5.90E-24, respectively) and higher CT-pro-ET-1 levels (P=1.23E-122 and P=1.26E-67, respectively). Epistasis analyses showed a significant interaction between the sentinel SNP of F12 and KLKB1 for both traits. In addition, a variant near the ADM gene (rs2957692) was associated with MR-pro-ADM (P=1.05E-12) and a variant in EDN-1 (rs5370) was associated with CT-pro-ET-1 (P=1.49E-27). The total phenotypic variation explained by the genetic variants was 7.2% for MR-pro-ADM and 14.6% for CT-pro-ET-1. KLKB1 encodes plasma kallikrein, a proteolytic enzyme known to cleave high-molecular-weight kininogen to bradykinin and prorenin to renin. We cloned the precursors of ADM and ET-1 and demonstrated that purified plasma kallikrein can cleave these recombinant proteins into multiple smaller peptides. The discovery of genetic variants in the kallikrein-kinin system and in the genes encoding pre-pro-ET-1 and pre-pro-ADM provides novel insights into the (co-)regulation of these vasoactive peptides in the vascular system.
Asunto(s)
Adrenomedulina/sangre , Endotelina-1/sangre , Estudio de Asociación del Genoma Completo , Fragmentos de Péptidos/sangre , Precursores de Proteínas/sangre , Adrenomedulina/genética , Adulto , Anciano , Endotelina-1/genética , Epistasis Genética , Femenino , Humanos , Sistema Calicreína-Quinina/genética , Calicreínas/genética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/genética , Polimorfismo de Nucleótido Simple , Precursores de Proteínas/genética , Población Blanca/genética , Población Blanca/estadística & datos numéricosRESUMEN
OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.