However, the genetic polymorphisms in coding region alter the function or structure of encoded proteins. Those alterations can directly influence the phenotype of diseases. Therefore we assumed that the genetic polymorphism at codon 10 may affect the production or activity of TGF-��1, because it presents within the coding region. The function of a signal sequence moreover is translocation of newly synthesized proteins across the membrane of the endoplasmic reticulum (17). It consists of three regions: a positively charged NH2-terminal region, a central hydrophobic core, and a polar COOH-terminal region (18). The amino acid coded by codon 10 of TGF-��1 gene is located in the central hydrophobic core and influences on the overall hydrophobicity of core sequence (4).

Therefore, the change of a neutral proline to hydrophobic leucine residue disrupts the structure of the region, alters transportation across endoplasmic reticulum (4), and may affect the production or activity of TGF-��1. The serum TGF-��1 levels were not measured in present study, because TGF-��1 is locally synthesized in the liver and may not reach systemic circulation for measuring. In addition, because platelet is the main source of serum TGF-��1, the serum levels of TGF-��1 do not always reflect its production in liver (5). Therefore, the analysis of TGF-��1 mRNA and protein expression in the liver are required for evaluating phenotypic differences according to the genetic polymorphisms. TGF-��1 was also associated with the development of HCC (19) and the L/L genotype at codon 10 in TGF-��1 was associated with the development of HCC (7, 10).

In the present study, HCC was present in 58% of patients of LC group, and the fact might influence on the results of this study. However, 70-90% of the patients with HBsAg positive HCC had already underlying cirrhosis (19). In addition, when cirrhotic patients without HCC were selected for analysis, the L/L genotype was still a significant risk factor for the development of cirrhosis. Liver fibrosis is a highly complex disease process in which multiple genes interact with viral and environmental risk factors. Among them, age is a major risk factor for the development of cirrhosis irrespective of any etiology. In order to exclude the influence of age factor, present study’s inclusion criteria restricted the age Drug_discovery of patients over 50 yr old. The reasons why present study chose 50 yr old for age were; first, cirrhosis was generally diagnosed around this age (20) and second, it is not common that chronic HBV carriers remain chronic hepatitis without cirrhosis over this age in Korean population (personal experience). The longer duration of HBV infection is also an important risk factor of cirrhosis.