Clinical Genetics and Screening for Pulmonary Fibrosis

肺纤维化的临床遗传学和筛查

基本信息

批准号：
10542373
负责人：
GARY MATTHEW HUNNINGHAKE
金额：
$ 138.52万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542373
关键词：
Acceleration Address Algorithms Awareness Biology Candidate Disease Gene Caring Chromosome Mapping Clinic Clinical Clinical Research Clinical Trials Data Detection Development Diagnosis Disease Disease Progression Early Diagnosis Environmental Exposure Ethnic Origin Ethnic Population First Degree Relative Future Genes Genetic Genetic Variation Genomic approach Genomics Goals Grant High Prevalence Interstitial Lung Diseases Length Lung Malignant Neoplasms Measures Medical Medical Genetics Medicine Methods Modeling Mucins Network-based Pathogenicity Patients Pharmacotherapy Physiological Play Population Population Heterogeneity Positioning Attribute Predictive Factor Predisposition Prevalence Process Prognosis Pulmonary Fibrosis Pulmonary function tests Registries Rejuvenation Relative Risks Reproducibility Risk Role Sample Size Site Test Result Therapeutic Intervention Trans-Omics for Precision Medicine Translational Research Validation Variant Work antifibrotic treatment biobank chest computed tomography clinical practice cohort college diagnostic value disorder risk early screening ethnic diversity exome experience fibrotic lung follow-up gene discovery gene network genetic information genetic testing genetic variant high risk idiopathic pulmonary fibrosis improved interest interstitial loss of function mortality multi-racial novel polygenic risk score proband prognostic value prognostication promoter public health priorities pulmonary function pulmonary function decline racial diversity racial population recruit risk prediction screening telomere transcriptomics

项目摘要

7. Project Summary The primary goal of this proposal is to develop an effective approach to screening for early stages of pulmonary fibrosis by assessing the diagnostic and prognostic value of clinical, environmental, genetic and genomic factors in at-risk relatives of patients with idiopathic pulmonary fibrosis (IPF). IPF, the most common and severe form of pulmonary fibrosis has a mortality rate comparable to that of many end-stage malignancies. Although IPF has historically been unresponsive to pharmacotherapy, recent studies have finally demonstrated that medical therapy can reduce the rate of decline in lung function, particularly when started early in the course of disease. In the prior grant cycle of this application we demonstrated that first-degree relatives were at high-risk to develop early stages of pulmonary fibrosis and that genetic testing helped to improve risk prediction. Based on these findings, we hypothesize that we will continue to observe a high prevalence of early pulmonary fibrosis in at-risk relatives; that we will be able to develop a clinically useful screening algorithm that combines key clinical, genetic, genomic, and environmental features for the early detection and prognostication of interstitial lung abnormalities (ILA) and/or pulmonary fibrosis in populations of diverse ethnic backgrounds; and that a subset of genes whose reduced expression predicts accelerated disease progression harbor pathogenic variants that help to drive this process. To assess these hypotheses, we propose the following Specific Aims: Aim 1) Develop an algorithm that can be used in clinical practice to identify relatives at the highest risk for pulmonary fibrosis, Aim 2) Prognosis: Define the baseline clinical, genetic, and genomic features in relatives found to have ILA that best predict their risk of disease progression, and 3) Identify novel genetic variants that contribute to pulmonary fibrosis susceptibility using an integrative genomics approach. In addition to providing a greater understanding of the role of that genetic variation plays in the development of IPF, the results from this study will motivate a clinical trial evaluating the use of screening and early therapeutic intervention in relatives at high-risk to develop IPF.

七、项目概要该提案的主要目标是开发一种有效的方法来筛选通过评估肺纤维化的诊断和预后价值来评估肺纤维化的早期阶段患者高危亲属的临床、环境、遗传和基因组因素特发性肺纤维化（IPF）。 IPF，最常见和最严重的形式肺纤维化的死亡率与许多终末期患者的死亡率相当恶性肿瘤。尽管IPF历来对药物治疗没有反应，最近的研究最终证明药物治疗可以降低患病率肺功能下降，尤其是在病程早期就开始下降。在在本申请的先前资助周期中，我们证明一级亲属处于发生早期肺纤维化的风险很高，基因检测有助于改进风险预测。基于这些发现，我们假设我们将继续观察到高危亲属中早期肺纤维化的患病率较高；我们将成为能够开发出一种临床上有用的筛查算法，该算法结合了关键的临床、遗传、用于早期检测和预测的基因组和环境特征不同人群的间质性肺异常（ILA）和/或肺纤维化种族背景；表达减少的基因子集预测加速的疾病进展含有有助于推动这一趋势的致病变异过程。为了评估这些假设，我们提出以下具体目标：目标 1) 开发一种可用于临床实践的算法来识别亲属肺纤维化风险最高，目标 2) 预后：定义临床基线，发现患有 ILA 的亲属的遗传和基因组特征最能预测他们的风险疾病进展，以及 3) 识别导致肺部疾病的新遗传变异使用综合基因组学方法评估纤维化易感性。除了提供更好地了解遗传变异在发育中所起的作用 IPF，这项研究的结果将激发一项评估使用的临床试验对罹患 IPF 高风险的亲属进行筛查和早期治疗干预。