Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF.

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated.

variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis.

Background: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT.

Methods: First-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest.

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. We performed deep targeted resequencing (3.

Use of a molecular classifier to identify usual interstitial pneumonia in conventional transbronchial lung biopsy samples: a prospective validation study.

Background: In the appropriate clinical setting, the diagnosis of idiopathic pulmonary fibrosis (IPF) requires a pattern of usual interstitial pneumonia to be present on high-resolution chest CT (HRCT) or surgical lung biopsy. A molecular usual interstitial pneumonia signature can be identified by a machine learning algorithm in less-invasive transbronchial lung biopsy samples. We report prospective findings for the clinical validity and utility of this molecular test.

Usual Interstitial Pneumonia Can Be Detected in Transbronchial Biopsies Using Machine Learning.

Rationale: Usual interstitial pneumonia (UIP) is the histopathologic hallmark of idiopathic pulmonary fibrosis. Although UIP can be detected by high-resolution computed tomography of the chest, the results are frequently inconclusive, and pathology from transbronchial biopsy (TBB) has poor sensitivity. Surgical lung biopsy may be necessary for a definitive diagnosis.

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP.

Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis.

Rationale: Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF).

Objectives: To identify novel variants in DSP associated with IPF and to characterize the relationship of these IPF sequence variants with DSP gene expression in human lung.

Methods: A chromosome 6 locus (7,370,061-7,606,946) was sequenced in 230 subjects with IPF and 228 control subjects.

Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.

Background: Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs.

Results: Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons.

Classification of usual interstitial pneumonia in patients with interstitial lung disease: assessment of a machine learning approach using high-dimensional transcriptional data.

Background: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease that distorts pulmonary architecture, leading to hypoxia, respiratory failure, and death. Diagnosis is difficult because other interstitial lung diseases have similar radiological and histopathological characteristics. A usual interstitial pneumonia pattern is a hallmark of idiopathic pulmonary fibrosis and is essential for its diagnosis.

Rare variants in RTEL1 are associated with familial interstitial pneumonia.

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.

Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.

Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA.

Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.

Rationale: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.

Objectives: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.

Methods: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.

Familial and sporadic idiopathic pulmonary fibrosis: making the diagnosis from peripheral blood.

Background: Peripheral blood biomarkers might improve diagnostic accuracy for idiopathic pulmonary fibrosis (IPF).

Results: Gene expression profiles were obtained from 89 patients with IPF and 26 normal controls. Samples were stratified according to severity of disease based on pulmonary function.

Bronchoscopic cryobiopsy for the diagnosis of diffuse parenchymal lung disease.

Background: Although in some cases clinical and radiographic features may be sufficient to establish a diagnosis of diffuse parenchymal lung disease (DPLD), surgical lung biopsy is frequently required. Recently a new technique for bronchoscopic lung biopsy has been developed using flexible cryo-probes. In this study we describe our clinical experience using bronchoscopic cryobiopsy for diagnosis of diffuse lung disease.

Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.

Importance: Current prediction models of mortality in idiopathic pulmonary fibrosis (IPF), which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials.

Objective: To determine whether the MUC5B promoter polymorphism (rs35705950), previously reported to be associated with the development of pulmonary fibrosis, is associated with survival in IPF.

MUC5B promoter polymorphism and interstitial lung abnormalities.

Background: A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population.

Methods: We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT).

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.

High-resolution CT scan findings in familial interstitial pneumonia do not conform to those of idiopathic interstitial pneumonia.

Background: The aim of this study was to describe the high-resolution CT (HRCT) scan features that characterize familial interstitial pneumonia (FIP).

Methods: FIP was defined by the presence of two or more cases of probable or definite idiopathic interstitial pneumonia (IIP) in individuals related within three degrees. The cases were collected consecutively from three centers.

Familial idiopathic interstitial pneumonia: histopathology and survival in 30 patients.

Context: Familial idiopathic interstitial pneumonia (F-IIP) describes the unexplained occurrence of diffuse parenchymal lung disease in related individuals. Prevailing wisdom suggests that the histopathology of F-IIP is indistinguishable from that of idiopathic pulmonary fibrosis, namely, usual interstitial pneumonia (UIP).

Objective: To define the histopathology of F-IIP in lung tissue samples.

Molecular mechanisms in progressive idiopathic pulmonary fibrosis.

There is clear evidence that environmental exposures and genetic predisposition contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoking increases the risk of developing IPF several-fold, as do other exposures such as metal-fume and wood-dust exposure. Occupations that increase the risk of IPF are agricultural work, hairdressing, and stone polishing, supporting the role of environmental exposure in disease pathogenesis.

The peripheral blood transcriptome identifies the presence and extent of disease in idiopathic pulmonary fibrosis.

Rationale: Peripheral blood biomarkers are needed to identify and determine the extent of idiopathic pulmonary fibrosis (IPF). Current physiologic and radiographic prognostic indicators diagnose IPF too late in the course of disease. We hypothesize that peripheral blood biomarkers will identify disease in its early stages, and facilitate monitoring for disease progression.