Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study.
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.
Romero-Gómez
Manuel
M
Hospital Universitario de Valme, Universidad de Sevilla, Spain. mromerogomez@us.es
Jover
María
M
Del Campo
José A
JA
Royo
José L
JL
Hoyas
Elena
E
Galán
José J
JJ
Montoliu
Carmina
C
Baccaro
Eugenia
E
Guevara
Mónica
M
Córdoba
Juan
J
Soriano
Germán
G
Navarro
José M
JM
Martínez-Sierra
Carmen
C
Grande
Lourdes
L
Galindo
Antonio
A
Mira
Emilia
E
Mañes
Santos
S
Ruiz
Agustín
A
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
D005972:Glutaminase