Genetic polymorphism at codon 10 of the transforming growth factor-beta1 gene in patients with alcoholic liver cirrhosis / 대한간학회지

BACKGROUND/AIMS: Transforming growth factor beta1 (TGF-beta1) is a key cytokine in the production of extracellular matrix. A genetic polymorphism at codon 10 of the TGF-beta1 gene is associated with liver fibrosis. We investigated the effect of genetic polymorphisms at codon 10 on the development of alcoholic liver cirrhosis (ALC). METHODS: In total, 119 controls and 182 patients with ALC, were enrolled in the study. Clinical and laboratory data including total lifetime alcohol intake were collected at enrollment. The genotype at codon 10 was determined for each patient by single-strand conformation polymorphism. RESULTS: There were three types of genetic polymorphism at codon 10: homozygous proline (P/P), heterozygous proline/leucine (P/L), and homozygous leucine (L/L). Among the controls, the proportions of P/P, P/L, and L/L were 26.1%, 44.5%, and 29.4%, respectively in the ALC group, these proportions were 23.1%, 43.4%, and 33.5%, respectively. The genotype distribution did not differ between the controls and the ALC group. In the ALC group, age, total lifetime alcohol intake, and distribution of Child-Pugh class did not differ with the genotype. Of the male patients with ALC (n=164), the proportions of P/P, P/L, and L/L were 20.1%, 44.5%, and 35.4%, respectively the genotype distribution did not differ between the male controls and the male ALC patients. CONCLUSIONS: The genotype at codon 10 in TGF-beta1 does not appear to influence the development of ALC. Further study is needed to investigate other genetic factors that influence the development of ALC in patients with chronic alcohol intake.

Genetic Polymorphisms of Alcohol-metabolizing Enzymes and Cytokines in Patients with Alcohol Induced Pancreatitis and Alcoholic Liver Cirrhosis / 대한소화기학회지

BACKGROUND/AIMS: Susceptibility to organ damage induced by alcohol may be related to inherited variations (polymorphisms) in alcohol-metabolizing enzymes, or polymorphisms affecting cytokines. The aim of this study was to compare the genotype and allelic frequencies of ADH2, ADH3, ALDH2, cytochrome P450-2E1, IL-1, IL-6, IL-8 and tumor necrosis factor-alpha in patients with alcoholic pancreatitis and alcoholic liver cirrhosis with those of controls. METHODS: We determined the polymorphism of genes of the above-mentioned alcohol-metabolizing enzymes and cytokines in 29 alcoholic pancreatitis patients (AP), 22 alcoholic liver cirrhosis patients (LC) and 100 healthy blood donors (control). The genotypes were characterized by restriction fragment length polymorphism after amplification of genomic DNA by polymerase chain reaction. RESULTS: The allelic frequency of CYP2E1*c2 was significantly different in three groups (AP: LC: Control=0.224: 0.136: 0.320, p<0.05). There was no significant difference in the other genotypes or allelic frequencies of the three groups. The allelic frequencies of CYP2E1*c2 and ALDH2*2 were more frequent in the control than patients with alcoholic liver cirrhosis (LC: Control=0.136: 0.320, p<0.05, LC: Control= 0.114: 0.265, p<0.05). Allelic frequencies of ADH2 was statisitcally different between LC and control (ADH2*1; LC: Control=0.727: 0.495, ADH2*2; 0.227: 0.360, ADH2*3; 0.046: 0.145, p<0.05). CONCLUSIONS: There was no difference in the frequencies of genotype and allele of enzymes and cytokines among the three groups. However, frequency of ADH2*1 was significantly higher and those of CYP2E1*c2 and ALDH2*2 were significantly lower than LC group than control.

Estudio de la asociación alélica entre los polimorfismos de los genes de colágena tipo I (COLIA1 y COLIA2) y daño hepatico de tipo alcohólico / Allelic association study between collagen type I (COLIA1 and COLIA2) polymorphisms and alcohol liver disease

Se desconoce la cantidad de duración del consumo excesivo de alcohol que lleva a la generación del daño hepático. Mientras que en la mayoría de los individuos que abusan del alcohol se desarrolla hígado graso, sólo en una pequeña proporción se genera inexorablemente un daño grave (cirrosis o hepatitis alcohólica). En numerosos estudios se indica la existencia de factores genéticos asociados a la susceptibilidad de desarrollar daño hepático inducido por el alcohol. La producción de la colágena tipo I es particularmente abundante en la cirrosis hepática: por esta razón, los genes que codifican para esta proteína se consideran como "candidatos" importantes en el estudio de la predisposición genética a esta enfermedad. El objetivo de este trabajo es el de analizar los polimorfismos para los genes humanos de colágena tipo I (COLIA1 y COLIA2) en muestras de alcohólicos que presentan o no cirrosis, para probar la hipótesis de que estas variantes pudieran estar asociadas (y probablemente contribuir) a la predisposición a desarrollar el daño hepatico inducido por el consumo excesivo de etanol. Se estudiaron 74 pacientes mexicanos que reconocieron beber 80 g o más de etanol al día durante un lapso de por lo menos 10 años. El diagnóstico o, en su caso, la exclusión de cirrosis, fue establecido por medio de su historia clínica, pruebas de laboratorio, ultrasonido y, en algunos casos, biopsia hepática. Se analizaron los genotipos de 3 diferentes polimorfismos (dos en el gene COLIA1 y uno en el COLIA2), mediante la amplificación de las regiones correspondientes por PCR. No se observaron diferencias en las frecuencias de los alelos y los genotipos entre ambos grupos. Sin embargo, la frecuencia del alelo A2 del sistema polimórfico Rsal/COLIA1 fue mayor en los alcohólicos que en un grupo de sujetos sanos. En conclusión, los polimorfismos analizados no parecen estar asociados a un mayor riesgo o susceptibilidad de desarrollar daño hepático inducido por el alcohol. No se puede descartar que otras variantes no analizadas en este trabajo pudieran estar relacionadas con mutaciones cercanas, las cuales pudieran modificar la biosíntesis o estructura de la colágena tipo I, por medio de la interacción directa o indirecta del alcohol