Manuel Romero-Gómez, MD, PhD; María Jover, PhD; José A. Del Campo, PhD; José L. Royo, PhD; Elena Hoyas, MD; José J. Galán, PhD; Carmina Montoliu, PhD; Eugenia Baccaro, MD; Mónica Guevara, MD, PhD; Juan Córdoba, MD, PhD; Germán Soriano, MD, PhD; José M. Navarro, MD; Carmen Martínez-Sierra, MD, PhD; Lourdes Grande, MD, PhD; Antonio Galindo, MD, PhD; Emilia Mira, PhD; Santos Mañes, PhD; Agustín Ruiz, MD, PhD
Romero-Gómez M, Jover M, Del Campo JA, Royo JL, Hoyas E, Galán JJ, et al. 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. 2010;153:281-288. doi: 10.7326/0003-4819-153-5-201009070-00002
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Published: Ann Intern Med. 2010;153(5):281-288.
Hepatic encephalopathy is a major complication of cirrhosis and is associated with a poor prognosis.
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.
Outpatient clinics in 6 Spanish hospitals.
109 consecutive patients with cirrhosis in the estimation cohort, 177 patients in the validation cohort, and 107 healthy control participants.
Patients were followed every 3 or 6 months until the development of hepatic encephalopathy or liver transplantation, death, or the end of the study.
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: Childâ€“Turcotteâ€“Pugh stage (hazard ratio [HR], 1.6 [95% CI, 1.29 to 1.98]; PÂ = 0.001), minimal hepatic encephalopathy (HR, 3.17 [CI, 1.42 to 7.09]; PÂ = 0.006), and having 2 long alleles of the microsatellite (HR, 3.12 [CI, 1.39 to 7.02]; PÂ = 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]; PÂ = 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.
Other genes and allelic variants might be involved in the clinical expression of hepatic encephalopathy.
This study identifies a genetic factor that is associated with development of hepatic encephalopathy in patients with cirrhosis.
Instituto de Salud Carlos III, Spanish Ministry of Health.
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Gastroenterology/Hepatology, Neurology, Encephalopathy, Liver Disease.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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