Genetic Epidemiology of HCV-related Liver Disease

描述（由申请人提供）： 据估计，400万丙型肝炎感染（HCV）的美国人中有20-30%预计在感染2-3年后发展为晚期纤维化和肝硬化。暴露于纤维化促进风险因素（如酗酒）的差异可能解释了纤维化风险的一些差异。然而，目前的研究表明，遗传因素也可能影响HCV患者晚期纤维化的风险。研究一再表明与晚期肝病发展相关的两个因素是男性性别和腹部肥胖。然而，具体的作用遗传因素，包括那些与男性性激素受体或雄激素受体（AR）和胰岛素抵抗（IR）与腹部肥胖，可能在纤维化的风险仍然不清楚。这项研究的目的是确定AR和IR基因的变化在增加晚期纤维化风险中的作用。相关的具体目的是：1）识别和收集大量有代表性的HCV感染男性退伍军人队列的数据; 2）检验与IR相关的基因的“高风险”变体单独或与腹部肥胖相关的基因的“高风险”变体增加纤维化风险的假设;和3）检验与AR相关的基因的“高风险”变体也增加纤维化风险的假设。目标1将采用标准流行病学方法进行队列识别，并将在Michael E. DeBakey VA.目的2和3将通过一项病例对照研究来解决，在该研究中，将患有晚期纤维化的队列成员（病例）与患有轻度纤维化的队列成员（对照）进行比较。研究计划，教学培训和优秀的指导环境将共同努力，使主要研究者获得新的技能，并完善现有的技能，在开发和执行新的遗传流行病学研究，使她能够发展成为一个独立的研究者在遗传流行病学的慢性肝脏和消化系统疾病。

DESCRIPTION (provided by applicant): An estimated 20-30% of the four million Americans with hepatitis C infection (HCV) are projected to develop advanced fibrosis and cirrhosis after 2-3 decades of infection. Differences in exposure to fibrosis-promoting risk factors like alcohol abuse likely explain some of this difference in fibrosis risk. However, current research suggests that genetic factors may also influence the risk of advanced fibrosis in HCV patients. Two factors that research has repeatedly shown to be associated with development of advanced liver disease are male gender and abdominal obesity. However, the specific role genetic factors, including those related to male sex hormone receptor or androgen receptors (AR) and to insulin resistance (IR) associated with abdominal obesity, may play in fibrosis risk remains unclear. The goal of the proposed study is to ascertain the role that changes in AR and IR genes play in increasing risk of advanced fibrosis. The associated specific aims are: 1) to identify and collect data on a large and representative cohort of male veterans with HCV infection; 2) to test the hypothesis that 'high risk" variants of genes related to IR either alone or in conjunction with abdominal obesity increase fibrosis risk; and 3) to test the hypothesis that 'high risk' variants of genes related to AR also increase fibrosis risk. Aim 1 will be accomplished with standard epidemiology methods for cohort identification and will be performed at the Michael E. DeBakey VA. Aims 2 and 3 will be addressed through a case-control study in which cohort members with advanced fibrosis (cases) are compared to those with mild fibrosis (controls). The research plan, didactic training and outstanding mentoring environment will work together to allow the principal investigator to acquire new skills as well as refine existing skills in the development and execution of novel genetic epidemiology studies, allowing her to develop into an independent investigator in genetic epidemiology of chronic liver and digestive disorders.