title: A genetic variant in the promoter of phosphate-activated glutaminase is associated with hepatic encephalopathy.
abstract: BACKGROUND
  Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. Recently, a microsatellite in the promoter region of the phosphate-activated glutaminase (GLS ) gene was associated with the risk of HE. The aim of the present study was to investigate, using the critical flicker frequency (CFF) test, whether the described GLS variant increases the risk of developing HE in patients with cirrhosis.
  
  
  METHODS
  We recruited 158 patients (66% men; mean age 59 years, range 23-86) with liver cirrhosis. Mean model for end-stage liver disease score was 13.8 (range 5-35); 48% of patients presented with Child-Pugh score B or C. The presence and severity of HE were determined by the CFF test, with frequencies ≤39 Hz denoting cases. GLS variants were genotyped by sequencing the microsatellite in the promoter region and were classified as short, long or short-long forms (depending on the length of the macrosatellite alleles).
  
  
  RESULTS
  In total, 53% of patients had abnormal CFF results (i.e. ≤39 Hz; range for entire cohort 26-57). The GLS microsatellite distribution amongst patients was short form (20%), long form (32%) and short-long form (48%) and was consistent with Hardy-Weinberg equilibrium. CFF values differed significantly between groups (P = 0.043). Carriers of the GLS long microsatellite had a significantly higher risk of HE according to multivariate analyses (odds ratio 3.23, 95% confidence interval 1.46-7.13, P = 0.004).
  
  
  CONCLUSIONS
  CFF results were significantly lower amongst carriers of the GLS long microsatellite. Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition.
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: L B
authors.initials: LB
authors.lastname: Mayer
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.|Laboratory of Metabolic Liver Diseases, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Grünhage
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Lammert
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: C S
authors.initials: CS
authors.lastname: Stokes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D014644:Genetic Variation; D005972:Glutaminase / Q000235:genetics*; D006501:Hepatic Encephalopathy / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: C579480:GLS protein, human; D005972:Glutaminase
keywords: ammonia; astrocyte; cirrhosis; critical flicker frequency; glutamine synthetase