Preclinical Pulmonary Fibrosis, an opportune rare disease cohort

点击翻译按钮获取中文摘要

ABSTRACT FDR from FIP Family Our proposed rare disease cohort focuses on a critical unmet public health need in (N=1000) interstitial pneumonia, to understand the etiology, natural history, and phenotypic N=650 Subcohort N=350 heterogeneity of preclinical pulmonary fibrosis (PrePF), before the lung is scarred irreversibly. Our overall hypothesis is that common genetic variants and 100 PrePF 50 PrePF environmental risk factors predispose to the development, natural history, 300 unaffected and phenotypic heterogeneity of PrePF, and that defining these risk factors will allow us to uncover the common and unique subtypes of PrePF that differ Case-Cohort at baseline in disease onset and progression. By leveraging our NHLBI-supported (150 Cases; 300 Unaffecteds) discoveries in PrePF, familial interstitial pneumonia (FIP), and idiopathic interstitial Figure 1. Relationship between pneumonia (IIP), and our NHLBI-supported cohort of FIP families, our proposal Subcohort and the original FIP seeks to explain how common genetic variants and the environment interact to cohort. Given the risk of PrePF FIP FDRs (15%), we anticipate result in the earliest stages of this highly morbid, phenotypically heterogeneous that 50 individuals in the disease. We will focus on first-degree relatives (FDRs) previously phenotyped as Subcohort will have PrePF at unaffected (N=2404) from our 1160 FIP families with two or more cases of baseline. Cases will be supplemented from the confirmed IIP. Within these 1160 FIP families, we will establish our rare disease remaining 650 subjects in the cohort of 1000 subjects by selecting up to two asymptomatic, previously phenotyped overall cohort so that our case- unaffected FDRs per family. To combine the advantages of our cohort with the cohort population at baseline should include 150 cases of efficiency of a nested case-control study, we will establish a case-cohort study and PrePF and 300 unaffecteds. compare 150 cases of PrePF to 300 unaffected controls (Figure 1). This approach will allow us to determine the individual and combined contributions of common genetic variants and environmental features that result in the development of PrePF. By focusing on the natural history of IIP, our results can be used to identify high-risk populations, early forms of the disease, factors associated with disease progression, and biological targets for drug development. Moreover, a natural history study can also identify critical biomarkers that can be diagnostic of early or established forms of the disease, prognostic of the course of a disease, predictive of treatment response, or useful in guiding patient selection and dose selection in drug development programs. Our proposal would establish a prospectively followed high-risk IIP cohort, will identify the genetic and environmental risk factors for PrePF, and will maximize the utility of this high-risk cohort for ancillary studies focused on primary and secondary prevention of IIP.