1/2 Prospective tReatment EffiCacy in IPF uSlng genOtype for Nac Selection (PRECISIONS) trial and Molecular Endophenotyping in Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases study

摘要 尽管是最常见和最致命的间质性肺疾病(ILD)，特发性肺纤维化 (IPF)的诊断和治疗仍然具有挑战性。IPF的诊断过程依赖于主观性 临床数据的解释，而目前的抗肝纤维化治疗采用“一刀切”的范例。 我们团队的成员一直站在开发组学方法的前沿，以诊断和确定 ILDS的预后。重要的是，我们确定了第一个药物基因组相互作用，表明IPF患者 在TOLLIP中，rs3750920 T/T基因型明显受益于NAC。对分子的需求非常迫切 定义IPF的分类，从而实现基于精度的管理。我们的长期目标是 ILD诊疗进入“精准医学时代”。在一种高度创新的方法中，我们拥有 与肺纤维化基金会(PFF)临床护理网络(CCN)和注册中心合作。这群人 招募了那些提供了广泛的基线表型和纵向结果数据的ILD患者， 生物样本，并同意被重新联系以进行未来的研究。我们的总体目标是 高效地在IPF中进行基于精确基因型的新颖试验，同时利用CCN及其独特的 收集生物样品以从分子上表征广泛的ILDS并鉴定IPF的遗传变异 风险。为了达到我们基于精确的ILD管理的目标，我们将完成三个补充的具体 目标。在目标1中，我们将确定NAC是否是IPF患者的有效治疗方法，其特点是精确度 基因分型方法。我们将与PFF合作，通过TOLLIP T/T确定PFF注册主体 开始随机选择200名IPF患者，然后在相同的临床地点招募新的受试者 以双盲方式接受NAC或安慰剂。这项研究名为《IPF的前瞻性治疗效果》 使用基因进行NAC选择(精度)“试验，将记录创新的”精度“的好处。 一种耐受性良好且价格低廉的针对特定基因的研究设计。在目标2中，我们将区分IPF 使用血液转录组学和蛋白质组学的无偏见组合来自非IPF ILDS。我们建议 进行rna-seq和蛋白质组学研究，以确定整个pff上的基因表达和蛋白质生物标志物。 注册队列。我们将定义用于区分IPF和非IPF ILD的“签名”。我们不偏不倚的方法 组学特征将被整合，以揭示定义单个疾病、预测疾病的组学风险分数 当然，以及对治疗的反应。在目标3中，我们将确定在IPF风险中发挥作用的基因变异。我们会 对整个PFF队列进行全基因组测序，以检测IPF和IPF的新遗传关联 ILD风险。有了足够的能力，我们将评估常见和罕见/不常见的变体，将其与 种族匹配的未患病病例，以及ILD队列之间的匹配，以达到我们的目标。这将确立 这是同类数据中最大的集合，并为所有“组学”数据建立数量性状基因座。我们建议的结果 实验将把ILD治疗，特别是IPF治疗，带入精准医学时代。

ABSTRACT Despite being the most frequent and deadly of the interstitial lung diseases (ILD), Idiopathic Pulmonary Fibrosis (IPF) remains challenging to diagnose and treat. The diagnostic process for IPF relies on subjective interpretations of clinical data while current antifibrotic therapies employ a “one size fits all” paradigm. Members of our team have been at the forefront of developing `omics approaches to diagnose and define prognosis in ILDs. Importantly, we identified the first pharmacogenomic interaction suggesting that IPF patients with TOLLIP rs3750920 T/T genotype strongly benefited from NAC. There is a critical need for molecular classifications that define IPF, thus allowing precision-based management. Our long-term goals are to move ILD diagnosis and therapy into the “era of precision medicine.” In a highly innovative approach we have partnered with the Pulmonary Fibrosis Foundation (PFF) Clinical Care Network (CCN) and Registry. This group has recruited ILD patients who have provided extensive baseline phenotypic and longitudinal outcome data, biological samples and have consented to be re-contacted for future research. Our overall objective is to efficiently conduct a novel, precision genotype-based trial in IPF while leveraging the CCN and its unique biospecimen collection to characterize a broad range of ILDs molecularly and identify genetic variants of IPF risk. To address our goal of precision-based ILD management, we will complete three complementary Specific Aims. In Aim 1 we will determine if NAC is an effective treatment in IPF patients characterized by a precision genotype approach. In partnership with the PFF, we will identify PFF registry subjects with the TOLLIP T/T genotype to begin randomizing 200 IPF patients followed by enrolling new subjects at the same clinical sites to receive NAC or placebo in a double-blind fashion. This study, the “Prospective tReatment EffiCacy in IPF uSIng genOtype for Nac Selection (PRECISIONS)” trial, will document the benefits of an innovative “precision” genotype-specific study design of a well-tolerated and inexpensive therapy. In Aim 2 we will distinguish IPF from non-IPF ILDs using unbiased combinations of blood transcriptomics and proteomics. We propose to conduct RNA-seq and proteomics to characterize gene expression and protein biomarkers on the entire PFF registry cohort. We will define “signatures” for distinguishing IPF from non-IPF ILDs. Our unbiased approaches to `omics traits will be integrated to reveal `omics risk scores that define individual diseases, predict disease course, and response to therapy. In Aim 3 we will identify genetic variants playing a role in IPF risk. We will conduct whole genome sequencing of the entire PFF cohort to detect novel genetic associations for IPF and ILD risk. With sufficient power, we will assess both common and rare/infrequent variants in comparison to ethnically matched un-afflicted cases, and between ILD cohorts to meet our objective. This will establish the largest collection of its kind and establish quantitative trait loci for all `omics' data. The results of our proposed experiments will move ILD management, and IPF therapy, in particular, into the precision medicine era.