Clinical Genetics and Screening for Pulmonary Fibrosis

7.项目总结 这项建议的主要目标是开发一种有效的方法来筛查 早期肺纤维化的诊断和预后价值 慢性粒细胞白血病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的死亡率相当。 恶性肿瘤。尽管IPF在历史上对药物治疗没有反应， 最近的研究终于证明，药物治疗可以降低糖尿病的发病率。 肺功能下降，尤指在病程早期开始时。在 在这项申请的前一个拨款周期中，我们证明了一级亲属在 发生早期肺纤维化的高风险，基因检测有助于 提高风险预判水平。基于这些发现，我们假设我们将继续 观察高危亲属早期肺纤维化的高患病率；我们将 能够开发临床上有用的筛查算法，将关键的临床、遗传、 用于早期检测和预测的基因组和环境特征 不同类型人群的间质性肺异常(ILA)和/或肺纤维化 种族背景；基因的子集，其表达减少预示着 加速疾病进展的致病变异有助于推动这一进程 进程。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， 被发现患有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)识别导致肺疾病的新的基因变异 使用综合基因组学方法的纤维化易感性。除了提供 更好地理解遗传变异在糖尿病的发生发展中的作用 IPF，这项研究的结果将推动一项临床试验，评估 对高危亲属进行筛查和早期治疗干预，以发展成IPF。

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.