Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study.

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.

• Authors: Manuel Romero-Gómez, María Jover, José A Del Campo, José L Royo, Elena Hoyas, José J Galán, Carmina Montoliu, Eugenia Baccaro, Mónica Guevara, Juan Córdoba, Germán Soriano, José M Navarro, Carmen Martínez-Sierra, Lourdes Grande, Antonio Galindo, Emilia Mira, Santos Mañes, Agustín Ruiz
• Journal: Annals of internal medicine (Ann Intern Med) Vol. 153 Issue 5 Pg. 281-8 (Sep 07 2010) ISSN: 1539-3704 [Electronic] United States
• PMID: 20820037 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Glutaminase

Topics

• Aged
• Female
• Glutaminase (genetics)
• Hepatic Encephalopathy (etiology, genetics)
• Humans
• Liver Cirrhosis (complications, enzymology, genetics)
• Male
• Microsatellite Repeats (genetics)
• Middle Aged
• Mutation
• Promoter Regions, Genetic (genetics)
• Risk Factors