Genetic Modifiers of CF Liver Disease

描述（由申请人提供）：囊性纤维化（CF）的临床异质性仅部分由CFTR基因突变解释。大多数CF患者有肝功能障碍和局灶性胆汁性肝硬化（纤维化）的证据，这些患者的一个子集（5-7%）进展为严重肝病（CFLD），定义为门静脉高压症和多小叶肝硬化。CFLD的发生与特定的CFTR突变或其他生物标志物无关，目前还没有办法确定哪些CF婴儿会发生严重的肝脏疾病。 该建议的中心假设是CFLD的发展反映了非CFTR“修饰”等位基因（基因）的影响。本项目旨在通过转基因小鼠模型研究非CFTR基因与CFLD的相关性，并检测所选等位基因对肝纤维化的生物学效应。我们假设多个基因的多态性，每个基因都与肝脏疾病有概念上或机制上的联系，增加了发展为终末期CF肝脏疾病的风险，并且这些风险因素之间的相互作用将定义这种疾病的病理生理学。为了实现我们的目标，我们将研究400例有明确记录的严重肝病和门脉高压症的CF患者，以及400例性别和基因型匹配的年龄> 15岁且没有CFLD证据的CF患者。我们建议通过评估与CFLD发病机制相关的多个基因内的功能序列变异和单核苷酸多态性来确定CFLD发展的遗传危险因素。为了测试（“验证”）选定的遗传等位基因对肝纤维化的生物学效应（影响），我们将开发deltaF 508纯合的转基因小鼠，它们还表达另外的候选基因修饰等位基因。更好地定义CF中增加严重肝病风险的复杂基因型将允许早期识别易患终末期肝病的CF婴儿，从而允许测试目前可用的治疗方法。更好地了解CF中肝纤维化的病理生物学将确定新的靶点以预防（或减少）CFLD的发展。

DESCRIPTION (provided by applicant): The clinical heterogeneity in cystic fibrosis (CF) is only partly explained by mutations in the CFTR gene. Most CF patients have evidence of liver dysfunction and focal biliary cirrhosis (fibrosis), and a subset of these patients (5-7%) progresses to severe liver disease (CFLD), as defined by portal hypertension and multilobular cirrhosis. The development of CFLD has no relationship to specific CFTR mutations or other biomarkers, and there is currently no way to identify which CF infants will develop severe liver disease. The central hypothesis of this proposal is that the development of CFLD reflects the influence of non-CFTR "modifier" alleles (genes). This project is designed to identify associations between non-CFTR genes and CFLD, and test the biological effect of selected alleles on hepatic fibrosis in transgenic murine models. We hypothesize that polymorphisms in multiple genes, each with a conceptual or mechanistic link to liver disease, increase the risk for developing end-stage CF liver disease, and that interactions among these risk factors will define the pathophysiology of this disorder. To achieve our goals, we will study 400 CF patients with well-documented severe liver disease and portal hypertension, and 400 gender and genotype-matched CF patients > age 15 years who have no evidence of CFLD. We propose to identify heritable risk factors for the development of CFLD by evaluation of functional sequence variants within, and single nucleotide polymorphisms associated with, multiple genes associated with CFLD pathogenesis. To test ("validate") the biological effects (impact) of selected genetic alleles on liver fibrosis, we will develop transgenic mice homozygous for deltaF508, who are also expressing an additional candidate gene modifier allele. Better definition of the complex genotypes that increase risk for severe liver disease in CF will allow early identification of CF infants predisposed to develop end-stage liver disease, and thereby allow testing of currently available therapies. Better understanding of the pathobiology of hepatic fibrosis in CF will identify novel targets to prevent (or reduce) the development of CFLD.