Fibrogenic polymorphisms (TGF-beta, PAI-1, AT) in Mexican patients with established liver fibrosis. Potential correlation with pirfenidone treatment.
OBJECTIVE
The aim of this work was to establish a potential correlation between specific polymorphisms and presence of hepatic fibrosis in Mexican patients with established liver fibrosis (ELF). Second, necroinflammatory index improvement was correlated with Pirfenidone (PFD) treatment response and the same polymorphisms.


METHODS
We analyzed TGF-beta polymorphisms in codon 25, a single basepair guanine insertion-deletion polymorphism (4G/5G) for PAI-1 and angiotensin AT-6 single nucleotide polymorphism located in -6 promoter region. Twenty patients infected with either hepatitis C virus (HCV) (n = 13) or affected by alcohol consumption (n= 7) were included. Thirty subjects with no hepatic damage were included in control group. Blood samples for genomic DNA were obtained and plasminogen activator inhibitor-1 polymorphisms were done by polymerase chain reaction-artificial introduction of a restriction site, TGF-beta by polymerase chain reaction-amplification refractory mutation system and AT by polymerase chain reaction-restriction fragment length polymorphisms. Liver biopsies were obtained at baseline and after 12 months of PFD treatment.


RESULTS
Established liver fibrosis patients had the homozygote G/G TGF-beta genotype, which has been associated with increased development of fibrosis. None of our patients had the G/C genotype. All pure HCV and pure alcohol abuse subjects carried G/G TGF-beta genotype (100% vs 37% control) (P = 0.0006). The odds of having TGF-beta G/G genotype was 19.5 for HCV patients and 10.83 for alcohol consumption patients as compared with healthy subjects (P < 0.001). Established liver fibrosis patients had an improvement in necroinflammatory index after PFD treatment when correlated with plasminogen activator inhibitor-1 and angiotensinogen-6 genotypes.


CONCLUSIONS
Our data suggested that a combination of inherited polymorphisms increased the risk of advanced fibrosis in ELF patients. Pure HCV and pure alcohol consumption patients which were homozygous G/G carriers had 19.5- and 10.8-fold higher risk to develop advanced fibrosis respectively.
Armendáriz-Borunda
Juan
J
Institute of Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Jalisco, Mexico. armendbo@cucs.udg.mx
Rincón
Ana Rosa
AR
Muñoz-Valle
José Francisco
JF
Bueno-Topete
Miriam
M
Oregón-Romero
Edith
E
Islas-Carbajal
María Cristina
MC
Medina-Preciado
David
D
González-García
Ignacio
I
Bautista
C Alfredo
CA
García-Rocha
Sergio
S
Godoy
Jesús
J
Vázquez-Del Mercado
Mónica
M
Troyo-SanRoman
Rogelio
R
Arellano-Olivera
Inmaculada
I
Lucano
Silvia
S
Alvarez-Rodríguez
Adriana
A
Salazar
Adriana
A
D000328:Adult; D000368:Aged; D000808:Angiotensinogen / Q000235:genetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008800:Mexico; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D011728:Pyridones / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000235:genetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1; D011728:Pyridones; C051321:SERPINE1 protein, human; D016212:Transforming Growth Factor beta; D000808:Angiotensinogen; C093844:pirfenidone