Cirrhosis or highly advanced fibrosis is the 13th leading cause of death in the U.S. The leading cause of cirrhosis is the hepatitis C virus infection which affects more than 4 million Americans. Males with hepatitis C infection are much more likely to develop cirrhosis (up to one-third after several decades of infection) compared to females. However, there are unexplained inter-individual differences in risk as most HCV-infected males do not develop cirrhosis even after accounting for other risk factors like alcohol use. One potential explanatory factor may be genetic variation in the male sex hormone or androgen receptor (AR) gene. It regulates or co-regulates many other diverse genes, many with likely important roles in liver disease risk including controlling cellular inflammation and DNA repair. Experimental data suggests the AR and also its androgen ligands including the primary male sex hormone testosterone may play a role in increasing risk of liver cancer due to another viral infection, Hepatitis B virus. Our group recently demonstrated that increased testosterone levels were associated with significantly increased risk of advanced liver disease based on results of blood tests in male veterans with chronic hepatitis C infection. We will use an age-matched case-control study performed in 200 Caucasian male veterans with chronic HCV to evaluate the association between the androgen mediated AR signaling pathway spanning from germline genotype to hepatic gene expression and the risk of cirrhosis in male veterans with chronic hepatitis C infection. We hypothesize that changes in genotype or endophenotype associated with enhanced AR pathway signaling will be associated with increased risk of advanced fibrosis. The two specific aims of our proposal are: Specific Aim 1: To determine if germline variations in the AR gene and in key functionally-related genes in the androgen-mediated androgen receptor (AR) signaling pathway (e.g., 5-reductase 2 (SRD5A2)) are associated with risk of advanced biopsy-determined hepatic fibrosis in Caucasian males with chronic hepatitis C infection. Specific Aim 2: To determine if variation in hepatic AR gene expression or in related AR signaling pathway genes is associated with risk of biopsy-confirmed advanced hepatic fibrosis in Caucasian males with chronic hepatitis C infection. This study has the potential to expand our understanding of the etiology of advanced liver fibrosis in males in the background of hepatitis C infection, with implications for screening and targeted therapies. It will also extend my NIDDK-sponsored K01 research and training in genetic epidemiology of chronic digestive and liver diseases, and also provide foundational data needed to support an R01 application I plan to submit in K01 Year 5 to more fully examine these hypotheses.