title: 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.
  
  
  METHODS
  Cohort study.
  
  
  METHODS
  Outpatient clinics in 6 Spanish hospitals.
  
  
  METHODS
  109 consecutive patients with cirrhosis in the estimation cohort, 177 patients in the validation cohort, and 107 healthy control participants.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Other genes and allelic variants might be involved in the clinical expression of hepatic encephalopathy.
  
  
  CONCLUSIONS
  This study identifies a genetic factor that is associated with development of hepatic encephalopathy in patients with cirrhosis.
  
  
  BACKGROUND
  Instituto de Salud Carlos III, Spanish Ministry of Health.
authors.affiliation: Hospital Universitario de Valme, Universidad de Sevilla, Spain. mromerogomez@us.es
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gómez
authors.forename: María
authors.initials: M
authors.lastname: Jover
authors.forename: José A
authors.initials: JA
authors.lastname: Del Campo
authors.forename: José L
authors.initials: JL
authors.lastname: Royo
authors.forename: Elena
authors.initials: E
authors.lastname: Hoyas
authors.forename: José J
authors.initials: JJ
authors.lastname: Galán
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.forename: Eugenia
authors.initials: E
authors.lastname: Baccaro
authors.forename: Mónica
authors.initials: M
authors.lastname: Guevara
authors.forename: Juan
authors.initials: J
authors.lastname: Córdoba
authors.forename: Germán
authors.initials: G
authors.lastname: Soriano
authors.forename: José M
authors.initials: JM
authors.lastname: Navarro
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez-Sierra
authors.forename: Lourdes
authors.initials: L
authors.lastname: Grande
authors.forename: Antonio
authors.initials: A
authors.lastname: Galindo
authors.forename: Emilia
authors.initials: E
authors.lastname: Mira
authors.forename: Santos
authors.initials: S
authors.lastname: Mañes
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
mesh_terms: D000368:Aged; D005260:Female; D005972:Glutaminase / Q000235:genetics*; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D005972:Glutaminase