Genetic Epidemiology of HCV-related Liver Disease

描述(由申请人提供)： 据估计，在400万感染丙型肝炎(丙型肝炎)的美国人中，预计有20%-30%的人在感染20-30年后发展为晚期纤维化和肝硬变。暴露在酒精滥用等促进纤维化的危险因素中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丙型肝炎患者晚期纤维化的风险。研究一再表明，与晚期肝病的发生有关的两个因素是男性性别和腹部肥胖。然而，遗传因素，包括与男性性激素受体或雄激素受体(AR)相关的因素，以及与腹型肥胖相关的胰岛素抵抗(IR)，在纤维化风险中可能发挥的具体作用尚不清楚。这项拟议研究的目的是确定AR和IR基因的变化在增加晚期纤维化风险中所起的作用。相关的具体目标是：1)确定和收集大量有代表性的感染丙型肝炎病毒的男性退伍军人的数据；2)测试与胰岛素抵抗相关的基因的“高风险”变体单独或与腹部肥胖一起增加纤维化风险的假设；以及3)测试与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将通过队列鉴定的标准流行病学方法实现，并将在Michael E.DeBakey VA进行。目标2和目标3将通过病例对照研究来解决，在该研究中，对患有晚期纤维化(病例)的队列成员与轻度纤维化(对照)的成员进行比较。研究计划、教学培训和卓越的指导环境将共同努力，使首席研究员在开发和执行新的遗传流行病学研究方面获得新的技能，并完善现有技能，使她能够发展成为慢性肝脏和消化系统疾病遗传流行病学的独立研究员。

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.