Genetic Basis of Pulmonary Fibrosis

肺纤维化的遗传基础

• 批准号: 9276761
• 负责人: John Atlas Phillips III
• 金额: $ 42.94万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-19 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9276761
• 关键词: Bioinformatics; Biological; Candidate Disease Gene; Centromere; Code; Color; Coupled; Critical Pathways; DNA; Data; Data Set; Development; Diagnosis; Disease; Evolution; Family; Fibrosis; Funding; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Techniques; Genetic Variation; Genetic study; Genotype; Hamman-Rich syndrome; Human; Individual; Inheritance Patterns; Inherited; Interstitial Lung Diseases; Interstitial Pneumonia; Lead; Link; Lung; Medical Records; Messenger RNA; Methodology; Methods; Minor; Modeling; Morbidity - disease rate; Mutation; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; Population Control; Predisposition; Pulmonary Fibrosis; Records; Research Personnel; Resources; Risk; Sampling; Structure; Techniques; Therapeutic Intervention; Tissues; Variant; Work; analytical method; base; cohort; design; effective therapy; exome sequencing; genetic approach; genetic information; genetic pedigree; genetic risk factor; genetic variant; genome sequencing; innovation; kindred; mortality; new therapeutic target; next generation sequencing; novel; novel strategies; programs; racial and ethnic; rare variant; segregation; telomere; tool; whole genome

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.

项目总结 在最初的资助期间，我们在190个家庭中使用了完整的外显子组测序，到目前为止 确定了与家族性间质性肺炎(FIP)相关的5个新基因中的罕见变异。这些 包括端粒相关基因RTEL1和DKC1；G蛋白偶联受体GPR87；着丝粒 基因CENPN；和SYDE1。虽然人们普遍认为FIP的遗传风险是在常染色体上遗传的 主导(AD)时尚，我们的FIP家族的系谱建模现在表明，多达39%的家庭 可能有其他遗传方式，包括X连锁(XL)或常染色体隐性遗传(AR)。正在评估 基于这些替代遗传模型的遗传风险为识别其他基因提供了希望 增加FIP风险，正如我们在FIP中发现的XL DKC1突变所表明的那样。尽管我们已经确定 在最初的资助期与FIP相关的几个基因中的新的杂合稀有变体， 我们的发现表明，多种基因(不是单个基因或一小部分基因)的罕见变异起到了作用。 至FIP风险。这个问题，加上我们许多FIP家族在遗传信息方面的局限性，已经 需要新的途径和新的分析方法来识别FIP中的遗传风险因素。与.一起 南希·考克斯博士，项目2的新合作研究员，我们已经开始使用基因-组织表达(GTEx) 数据集来建立人类肺部和其他组织中基因表达的大规模预测因子，这可以是 应用于识别与疾病发病机制有关的基因。我们建议将此方法与 BioVU，这是Vanderbilt的一个独特资源，将未确认的医疗记录与基因分型的DNA联系起来 样本，以最大限度地增加本提案中遗传研究的信息量。除了在FIP学习外，我们还 我相信通过使用下一代测序技术来确定 散发性肺间质纤维化患者群体中FIP相关基因和通路的重要性。 基于与基因技术公司的一项新的合作安排，全基因组测序现在是可行的， 将致力于对散发性IPF背后的遗传因素有更全面的了解。这 该项目将调查FIP/IPF的发育受多种遗传因素影响的假设 导致疾病易感性的不同因素，包括主要影响的罕见变体和常见的 影响不大。确定两种类型的致病变异以及涉及的基因和生物途径 将阐明FIP和散发性IPF发病的关键机制。具体目标旨在： 1)确定以AD、AR或XL方式遗传的与FIP相关的罕见变体；2)调查 FIP相关基因和途径中罕见的、中间的和常见的遗传变异对 零星的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顺序 FIP和散发性IPF相关候选基因。连同该计划中的其他项目，这些 研究将通过识别新的疾病相关基因和变异来加强对FIP/IPF的了解。