Genetic Basis of Pulmonary Fibrosis

项目摘要 在最初的资助期间，我们在190个家庭中进行了全外显子组测序，到目前为止， 在5个与家族性间质性肺炎（FIP）相关的新基因中发现了罕见变异。这些 包括端粒相关基因RTEL 1和DKC 1; G蛋白偶联受体GPR 87;着丝粒 基因CENPN;和SYDE 1。虽然通常认为FIP的遗传风险是在常染色体中遗传的， 显性（AD）时尚，我们的FIP基因的谱系建模现在表明，多达39%的家庭， 可能有替代的遗传模式，包括X连锁（XL）或常染色体隐性（AR）。评价 基于这些替代性遗传模型的遗传风险为识别其他基因提供了希望， 导致FIP风险，正如我们在FIP中发现XL DKC 1突变所示。虽然我们已经确定 在最初的资助期间，与FIP相关的几个基因中的新杂合罕见变异， 我们的研究结果表明，多种基因中的罕见变异（不是单个基因或一小部分基因） FIP风险这个问题，沿着我们的许多FIP激酶的遗传信息的局限性， 需要新的方法和新的分析方法来识别FIP中的遗传风险因素。沿着 博士Nancy考克斯，项目2的新合作研究者，我们已经开始使用基因型组织表达（GTEx） 数据集来构建人类肺部和其他组织中基因表达的大规模预测因子， 用于鉴定疾病发病机制中的基因。我们建议采用这种方法， BioVU，这是范德比尔特的一个独特资源，它将去识别的医疗记录与基因型DNA联系起来 样本，以最大限度地提高本提案中遗传研究的信息量。除了在FIP的研究，我们 我认为，通过使用下一代测序技术来确定基因组， FIP相关基因和途径在较大的散发性IPF个体群体中的重要性。 根据与基因泰克公司的一项新的合作安排，全基因组测序现在是可行的， 将继续进行，以更全面地了解散发性IPF的遗传因素。这 该项目将研究FIP/IPF的发展受多种遗传因素影响的假设， 基因突变导致疾病易感性，包括主要效应的罕见变异和 轻微影响。确定两种类型的致病变异和相关的基因和生物学途径 将阐明FIP和散发性IPF发病机制的关键机制。具体目标旨在： 1)识别与FIP相关的罕见变异，这些变异以AD、AR或XL方式遗传; 2）研究FIP的遗传变异。 FIP相关基因和途径中的罕见、中间和常见遗传变异对 散发性IPF; 3）使用GTEx数据集、BioVU和先进的生物信息学方法来识别和确定优先级 与FIP和散发性IPF相关的候选基因。与该计划中的其他项目一起， 研究将通过识别新的疾病相关基因和变异体来增强对FIP/IPF的理解。

PROJECT SUMMARY During the initial funding period, we employed whole exome sequencing in 190 families and to date have identified rare variants in 5 new genes that are associated with familial interstitial pneumonia (FIP). These include telomere related genes RTEL1 and DKC1; the G protein-coupled receptor GPR87; the centromere gene CENPN; and SYDE1. While it is generally believed that genetic risk for FIP is inherited in an autosomal dominant (AD) fashion, pedigree modeling of our FIP kindreds now suggests that as many as 39% of families could have alternative modes of inheritance, including X-linked (XL) or autosomal recessive (AR). Evaluating genetic risk based on these alternative inheritance models offers promise for identifying additional genes that contribute to FIP risk, as illustrated by our finding of an XL DKC1 mutation in FIP. Although we have identified novel heterozygous rare variants in several genes that are associated with FIP during the initial funding period, our findings indicate that rare variants in a variety of genes (not a single gene or small set of genes) contribute to FIP risk. This issue, along with limitations in the genetic informativeness of many of our FIP kindreds, has necessitated new approaches and novel analytic methods for identifying genetic risk factors in FIP. Along with Dr. Nancy Cox, a new co-investigator in Project 2, we have begun to use Genotype-Tissue Expression (GTEx) datasets to build large-scale predictors of gene expression in human lungs and other tissues, which can be applied to identify genes involved in disease pathogenesis. We propose to use this approach coupled with BioVU, which is a unique resource at Vanderbilt that links de-identified medical records to genotyped DNA samples, to maximize informativeness of genetic studies in this proposal. In addition to studies in FIP, we believe it is important to broaden our focus by using next-generation sequencing techniques to determine the importance of the FIP-associated genes and pathways in the larger group of individuals with sporadic IPF. Based on a new collaborative arrangement with Genentech, whole genome sequencing is now feasible and will be pursued to develop a more complete understanding of genetic factors that underlie sporadic IPF. This project will investigate the hypothesis that development of FIP/IPF is influenced by multiple genetic factors that variably contribute to disease predisposition, including rare variants of major effect and common variants of minor effect. Identifying both types of disease-causing variants and the genes and biological pathways involved will elucidate critical mechanisms in the pathogenesis of FIP and sporadic IPF. Specific aims are designed to: 1) identify rare variants associated with FIP that are inherited in an AD, AR, or XL manner; 2) investigate the contribution of rare, intermediate, and common genetic variations in FIP associated genes and pathways to sporadic IPF; 3) use GTEx datasets, BioVU, and advanced bioinformatics approaches to identify and prioritize candidate genes associated with FIP and sporadic IPF. Together with other projects in this program, these studies will enhance understanding of FIP/IPF by identifying new disease-associated genes and variants.