Androgen Receptor Pathway and Risk of Hepatic Fibrosis in Hepatitis C

描述（由申请人提供）：肝硬化或高度晚期纤维化是美国第13大死亡原因，肝硬化的主要原因是丙型肝炎病毒感染，影响超过400万美国人。与女性相比，感染丙型肝炎的男性更有可能发展为肝硬化（感染数十年后高达三分之一）。然而，存在无法解释的个体间风险差异，因为即使考虑到酒精使用等其他风险因素，大多数丙型肝炎病毒感染的男性也不会发生肝硬化。一个潜在的解释因素可能是男性性激素或雄激素受体（AR）基因的遗传变异。它调节或共同调节许多其他不同的基因，其中许多基因可能在肝脏疾病风险中发挥重要作用，包括控制细胞炎症和DNA修复。实验数据表明，AR及其雄激素配体，包括主要的男性性激素睾酮，可能在另一种病毒感染乙肝病毒引起的肝癌风险增加中发挥作用。根据慢性丙型肝炎感染的男性退伍军人的血液测试结果，我们的小组最近证明，睾酮水平的升高与晚期肝病风险的显著增加有关。我们将在200名患有慢性丙型肝炎的高加索男性退伍军人中进行年龄匹配的病例对照研究，以评估雄激素介导的AR信号通路（从生殖系基因型到肝脏基因表达）与慢性丙型肝炎感染的男性退伍军人肝硬化风险之间的关系。我们假设与AR通路信号增强相关的基因型或内表型的变化与晚期纤维化的风险增加有关。具体目的1：确定AR基因和雄激素介导的雄激素受体（AR）信号通路中关键功能相关基因（如5¿-还原酶2 (SRD5A2)）的种系变异是否与慢性丙型肝炎感染的高加索男性晚期活组织检查确定的肝纤维化风险相关。特异性目的2：确定肝脏AR基因表达或相关AR信号通路基因的变异是否与慢性丙型肝炎感染白人男性活检证实的晚期肝纤维化风险相关。这项研究有可能扩大我们对丙型肝炎感染背景下男性晚期肝纤维化病因学的理解，对筛查和靶向治疗具有重要意义。它

DESCRIPTION (provided by applicant): 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.