Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study.
Ann Intern Med
; 153(5): 281-8, 2010 Sep 07.
Article
en En
| MEDLINE
| ID: mdl-20820037
ABSTRACT
BACKGROUND:
Hepatic encephalopathy is a major complication of cirrhosis and is associated with a poor prognosis.OBJECTIVE:
To identify mutations in the gene sequence for glutaminase in humans that could be responsible for the development of hepatic encephalopathy in patients with cirrhosis.DESIGN:
Cohort study.SETTING:
Outpatient clinics in 6 Spanish hospitals. PATIENTS 109 consecutive patients with cirrhosis in the estimation cohort, 177 patients in the validation cohort, and 107 healthy control participants. MEASUREMENTS Patients were followed every 3 or 6 months until the development of hepatic encephalopathy or liver transplantation, death, or the end of the study.RESULTS:
The genetic analyses showed that glutaminase TACC and CACC haplotypes were linked to the risk for overt hepatic encephalopathy. Mutation scanning of the glutaminase gene identified a section in the promoter region where base pairs were repeated (a microsatellite). Over a mean follow-up of 29.6 months, hepatic encephalopathy occurred in 28 patients (25.7%) in the estimation cohort. Multivariable Cox models were used to determine the following independent predictors Child-Turcotte-Pugh stage (hazard ratio [HR], 1.6 [95% CI, 1.29 to 1.98]; P = 0.001), minimal hepatic encephalopathy (HR, 3.17 [CI, 1.42 to 7.09]; P = 0.006), and having 2 long alleles of the microsatellite (HR, 3.12 [CI, 1.39 to 7.02]; P = 0.006). The association between 2 long alleles of the microsatellite and overt hepatic encephalopathy was confirmed in a validation cohort (HR, 2.1 [CI, 1.17 to 3.79]; P = 0.012). Functional studies showed higher luciferase activity in cells transfected with the long form of the microsatellite, which suggests that the long microsatellite enhances glutaminase transcriptional activity.LIMITATION:
Other genes and allelic variants might be involved in the clinical expression of hepatic encephalopathy.CONCLUSION:
This study identifies a genetic factor that is associated with development of hepatic encephalopathy in patients with cirrhosis. PRIMARY FUNDING SOURCE Instituto de Salud Carlos III, Spanish Ministry of Health.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
2_ODS3
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6_ODS3_enfermedades_notrasmisibles
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7_ODS3_muertes_prevenibles_nacidos_ninos
Problema de salud:
2_muertes_prevenibles
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6_cirrhosis
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6_digestive_diseases
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6_endocrine_disorders
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7_neonatal_care_health
Asunto principal:
Encefalopatía Hepática
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Regiones Promotoras Genéticas
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Glutaminasa
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Cirrosis Hepática
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Mutación
Tipo de estudio:
Clinical_trials
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Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Ann Intern Med
Año:
2010
Tipo del documento:
Article
País de afiliación:
España