RESUMEN
BACKGROUND: Recent genome-wide association studies have identified multiple loci that are associated with an increased risk of developing coronary artery disease (CAD). The impact of these loci on the disease severity and prognosis of ischemic heart failure due to CAD is currently unknown. METHODS: We undertook association analysis of 7 single nucleotide polymorphism (rs599839, rs17465637, rs2972147, rs6922269, rs1333049, rs501120, and rs17228212) at 7 well established CAD risk loci (1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21, and 15q22.33, respectively) in 3,320 subjects diagnosed with systolic heart failure of ischemic aetiology and participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) trial. The primary outcome was the composite of time to first event of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, secondary outcomes included mortality and hospitalization due to worsening heart failure. RESULTS: None of the 7 loci were significantly associated with the primary composite endpoint of the CORONA trial (death from cardiovascular cases, nonfatal myocardial infarction, and nonfatal stroke). However, the 1p13.3 locus (rs599839) showed evidence for association with all-cause mortality (after adjustment for covariates; HR 0.74, 95%CI [0.61 to 0.90]; P = 0.0025) and we confirmed the 1p13.3 locus (rs599839) to be associated with lipid parameters (total cholesterol (P = 1.1x10(-4)), low-density lipoprotein levels (P = 3.5 × 10(-7)) and apolipoprotein B (P = 2.2 × 10(-10))). CONCLUSION: Genetic variants strongly associated with CAD risk are not associated with the severity and outcome of ischemic heart failure. The observed association of the 1p13.3 locus with all-cause mortality requires confirmation in further studies.
Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Insuficiencia Cardíaca Sistólica/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
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
The blood group Vel was discovered 60 years ago, but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel. To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 × 10(-15)). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.
Asunto(s)
Antígenos de Grupos Sanguíneos/genética , Membrana Eritrocítica/metabolismo , Eritrocitos/inmunología , Eliminación de Gen , Homocigoto , Proteínas de la Membrana/genética , Sitios de Carácter Cuantitativo , Alelos , Animales , Biomarcadores/metabolismo , Antígenos de Grupos Sanguíneos/inmunología , Antígenos de Grupos Sanguíneos/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Eritrocitos/metabolismo , Eritrocitos/patología , Exoma/genética , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Isoanticuerpos/inmunología , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Embarazo , Pez Cebra/genéticaRESUMEN
MicroRNAs (miRNAs) are tiny, endogenous nucleotides that bind to mRNA and induce translation repression within metazoan cells. Since their discovery in 1993 in Caenorhabditis elegans and the demonstration of miRNAs in Homo sapiens in 2000, research has been fruitful in deciphering the role of these nucleotides in development, tissue homeostasis, and pathologic processes. In humans, around 700 human miRNA nucleotides have been verified, which interfere with 30% of all genes. Recently, the role of miRNA in cardiovascular research gained attention and the involvement of miRNAs in several cardiovascular diseases has been identified. In this review, we focus on the role of miRNAs in atherosclerosis and in particular on the potential role of miRNAs in the development of vulnerable atherosclerotic plaques. The role of miRNA in the main characteristics of these plaques, inflammation, angiogenesis, and apoptosis will be discussed. Finally, the future perspectives and miRNA-based diagnostic and therapeutic potentials will be highlighted.