RESUMEN
Liver fibrosis is the common consequence of chronic liver diseases (CLD). Recently liver stiffness measurements (LSM) ≥ 9.1 kPa, as determined by transient elastography (TE), were demonstrated to predict significant fibrosis (stages ≥ F2) in a population-based setting. The PNPLA3 (adiponutrin) p.I148M polymorphism enhances the risk of liver injury. The aim of our study was to investigate the association between the procholestatic ABCB4 polymorphism c.711A>T and LSM ≥ 9.1 kPa in humans as well as the interaction between ABCB4 and PNPLA3 in a mouse model of chronic cholestasis. Prospectively, we recruited 712 patients with CLD (278 women, age 50 ± 13 years) with available TE results; liver biopsy results were available in 165 individuals. The ABCB4 c.711 genotype was determined by PCR-based assays. PNPLA3 expression and liver injury were studied in Abcb4-/- mice and wild-type controls. Overall, median LSM in our cohort was 6.7 kPa, and 226 individuals had LSM ≥ 9.1 kPa. Carriers of the ABCB4 variant c.711A presented more frequently with LSM ≥ 9.1 kPa (OR = 1.33, P = 0.020) and FIB-4 score ≥ 2.67 (OR = 1.38, P = 0.040). The presence of the risk allele was associated (P = 0.002) with FIB-4. In a multivariate model, the ABCB4 variant (OR = 1.43, P = 0.047) as well as BMI (P = 0.043, OR = 1.04) and age (OR = 1.02, P < 0.010) were independent risk factors for fibrosis stage ≥ F2. Abcb4 deficiency in mice led to enhanced liver injury, coupled with a decrease (P = 0.020) of hepatic PNPLA3 expression. To conclude, the procholestatic variant ABCB4 c.711A>T might represent a new genetic risk factor for clinically significant liver fibrosis. Lower expression of PNPLA3 in fibrotic Abcb4-/- livers points to the interaction between phospholipid metabolism and PNPLA3 in progressive liver injury.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Cirrosis Hepática Experimental/genética , Cirrosis Hepática/genética , Hígado/metabolismo , Fosfolípidos/metabolismo , Polimorfismo de Nucleótido Simple , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Hígado/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/metabolismo , Cirrosis Hepática Experimental/metabolismo , Cirrosis Hepática Experimental/patología , Masculino , Ratones Noqueados , Persona de Mediana Edad , Fenotipo , Fosfolipasas A2 Calcio-Independiente/genética , Fosfolipasas A2 Calcio-Independiente/metabolismo , Medición de Riesgo , Factores de Riesgo , Adulto Joven , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Hematotoxicity is a life-threatening side effect of many chemotherapy regimens. Although clinical factors influence patient responses, genetic factors may also play an important role. We sought to identify genomic loci that influence chemotherapy-induced hematotoxicity by dosing Diversity Outbred mice with one of three chemotherapy drugs; doxorubicin, cyclophosphamide or docetaxel. We observed that each drug had a distinct effect on both the changes in blood cell subpopulations and the underlying genetic architecture of hematotoxicity. For doxorubicin, we mapped the change in cell counts before and after dosing and found that alleles of ATP-binding cassette B1B (Abcb1b) on chromosome 5 influence all cell populations. For cyclophosphamide and docetaxel, we found that each cell population was influenced by distinct loci, none of which overlapped between drugs. These results suggest that susceptibility to chemotherapy-induced hematotoxicity is influenced by different genes for different chemotherapy drugs.
Asunto(s)
Antineoplásicos/efectos adversos , Antecedentes Genéticos , Predisposición Genética a la Enfermedad/genética , Enfermedades Hematológicas/inducido químicamente , Enfermedades Hematológicas/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida/efectos adversos , Docetaxel/efectos adversos , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Distribución AleatoriaRESUMEN
Obstetric cholestasis (OC) is a cholestatic disorder with a prominent genetic background including variation in diverse hepatobiliary lipid transporters, such as ABCB4 (phospholipids) and ABCB11 (bile salts). Given a marked hepatocellular dysfunction in an OC patient indicated by > 40-fold rise in alanine aminotransferase activity and minor gamma-glutamyl transpeptidase increases, we performed genotyping of candidate gene variants associated with adult cholestatic phenotypes. Genetic analysis revealed the heterozygous ABCB4 mutation p.R590Q, the ABCB11 variant p.V444A and the lithogenic ABCG8 variant p.D19H. Aggregation of multiple hepatobiliary transporter variants is rare in OC, and may cooperate to negatively modulate hepatobiliary transport capacities.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/genética , Colestasis/genética , Complicaciones del Embarazo/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Adulto , Alanina Transaminasa/metabolismo , Colestasis/enzimología , Femenino , Variación Genética , Humanos , Embarazo , Complicaciones del Embarazo/enzimologíaRESUMEN
BACKGROUND: The incidence of acute coronary-artery occlusion among patients with sudden cardiac arrest outside of the hospital is unknown, and the role of reperfusion therapy has not been determined. We therefore performed immediate coronary angiography and angioplasty when indicated in survivors of out-of-hospital cardiac arrest. METHODS: Between September 1994 and August 1996, coronary angiography was performed in 84 consecutive patients between the ages of 30 and 75 years who had no obvious noncardiac cause of cardiac arrest. RESULTS: Sixty of the 84 patients had clinically significant coronary disease on angiography, 40 of whom had coronary-artery occlusion (48 percent). Angioplasty was attempted in 37 patients and was technically successful in 28. Clinical and electrocardiographic findings, such as the occurrence of chest pain and the presence of ST-segment elevation, were poor predictors of acute coronary-artery occlusion. The in-hospital survival rate was 38 percent. Multivariate logistic-regression analysis revealed that successful angioplasty was an independent predictor of survival (odds ratio, 5.2; 95 percent confidence interval, 1.1 to 24.5; P=0.04). CONCLUSIONS: Acute coronary-artery occlusion is frequent in survivors of out-of-hospital cardiac arrest and is predicted poorly by clinical and electrocardiographic findings. Accurate diagnosis by immediate coronary angiography can be followed in suitable candidates by coronary angioplasty, which seems to improve survival.
Asunto(s)
Angiografía Coronaria , Enfermedad Coronaria/diagnóstico , Paro Cardíaco/diagnóstico por imagen , Adulto , Anciano , Angioplastia Coronaria con Balón , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/terapia , Electrocardiografía , Femenino , Paro Cardíaco/etiología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Análisis de Supervivencia , SobrevivientesRESUMEN
To elucidate the pathogenesis of bronchospasm in congestive heart failure, we studied 23 patients with chronic impairment of left ventricular function due to coronary artery disease or dilated cardiomyopathy. In 21 of them we found marked bronchial hyperresponsiveness to methacholine. The mean dose (+/- SD) of methacholine that elicited a 20 percent decrease in the forced expiratory volume in one second (FEV1) was 421 +/- 298 micrograms, nearly the same as in patients with symptomatic asthma. In contrast, there was no bronchial response to methacholine in 9 of 10 patients who had coronary artery disease but normal left ventricular function. Administration of the bronchodilator albuterol led to a partial (43 percent) reversal of the methacholine-induced bronchial obstruction. In 12 patients, pretreatment with the alpha-adrenergic agonist methoxamine (10 mg by inhalation), a potent vasoconstrictor, fully prevented the methacholine-induced decrease in FEV1. The protective effect of methoxamine was blocked by the alpha-adrenergic antagonist phentolamine in all six patients who received this agent. We conclude that bronchial hyperresponsiveness to cholinergic agonists is frequent in patients with impaired left ventricular function and may contribute to the wheezy dyspnea commonly observed in such patients. The bronchoconstriction may be mediated at least in part by dilatation of the bronchial vessels.