Clinical Genetics and Screening for Pulmonary Fibrosis

7.项目摘要 该提案的主要目标是制定一种有效的方法， 肺纤维化的早期阶段，通过评估的诊断和预后价值， 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是最常见和严重的 肺纤维化的死亡率与许多终末期 恶性肿瘤虽然IPF历来对药物治疗无反应， 最近的研究最终证明，药物治疗可以降低 肺功能下降，特别是在病程早期开始时。在 在此申请的前一个赠款周期，我们证明了一级亲属在 高风险发展为肺纤维化的早期阶段，基因检测有助于 改善风险预测。基于这些发现，我们假设我们将继续 观察高危亲属中早期肺纤维化的高患病率;我们将 能够开发出一种临床上有用的筛选算法，该算法结合了关键的临床，遗传， 基因组和环境特征，用于早期检测和鉴定 间质性肺异常（ILA）和/或肺纤维化在不同的人群中 种族背景;而一个基因的子集，其减少的表达预测 加速的疾病进展携带致病性变异，有助于推动这一进程， 过程为了评估这些假设，我们提出了以下具体目标：目标1） 开发一种可用于临床实践的算法，以识别 肺纤维化的最高风险，目标2）预后：定义基线临床， 发现患有ILA的亲属中的遗传和基因组特征最能预测他们的风险， 疾病进展，和3）确定新的遗传变异，有助于肺 使用整合基因组学方法研究纤维化易感性。除了提供 更好地理解遗传变异在发展中的作用， IPF，本研究的结果将促使开展一项临床试验，评价 对有发生IPF高风险的亲属进行筛查和早期治疗干预。

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.