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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. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci., Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16))., Conclusions: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.

Rationale: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease of unknown etiology; its epidemiology in the United States has not been well characterized., Objective: To estimate the annual incidence and prevalence of idiopathic pulmonary fibrosis in the United States., Methods: Retrospective cohort design utilizing a large health care claims database spanning the period January 1996 through December 2000., Measurements and Main Results: Persons with idiopathic pulmonary fibrosis were identified based on diagnosis and procedure codes. Using broad case-finding criteria, prevalence was estimated to range from 4.0 per 100,000 persons aged 18 to 34 yr to 227.2 per 100,000 among those 75 yr or older; annual incidence was estimated to range from 1.2 to 76.4 per 100,000. Using narrow case-finding criteria, prevalence ranged from 0.8 to 64.7 per 100,000 persons; comparable figures for incidence were 0.4 to 27.1 per 100,000 persons. Extrapolating these rates to the overall United States' population, prevalence was estimated to be 42.7 per 100,000 (incidence, 16.3 per 100,000) using broad criteria; with narrow criteria, prevalence was estimated to be 14.0 per 100,000 (incidence, 6.8 per 100,000)., Conclusions: Our results suggest that idiopathic pulmonary fibrosis is probably more common in the United States than previously reported.

Rationale: High-resolution computed tomography (HRCT) is an integral aspect of the evaluation of patients with suspected idiopathic pulmonary fibrosis (IPF). However, few studies have evaluated its use in a large cohort., Objectives: To describe HRCT features in patients with mild to moderate IPF, compare diagnostic evaluations by a radiology core (three thoracic radiologists) with those by study-site radiologists, correlate baseline clinical and physiologic variables with HRCT findings, and evaluate their association with mortality., Methods: We assessed HRCT scans from patients with IPF (n = 315) enrolled in a randomized controlled study evaluating IFN-gamma1b., Measurements and Main Results: There was concordance between study-site and core radiologists regarding the diagnosis of IPF in 86% of cases. Diffusing capacity of carbon monoxide (DLCO) was the physiologic characteristic most highly correlated with HRCT findings. Multivariate analysis identified three independent predictors of mortality: a higher extent of fibrosis score increased the risk of death (p < 0.0001), whereas a higher percent-predicted DLCO (p = 0.004) and treatment assignment to IFN-gamma1b rather than placebo (p = 0.04) reduced the risk of death., Conclusions: A study-site diagnosis of IPF on HRCT was regularly confirmed by core radiologists. Extent of reticulation and honeycombing on HRCT is an important independent predictor of mortality in patients with IPF.

Background: Prospective data defining the clinical course in idiopathic pulmonary fibrosis (IPF) are sparse., Objective: To analyze the clinical course of patients with mild to moderate IPF., Design: Analysis of data from the placebo group of a randomized, controlled trial evaluating interferon-gamma1b., Setting: Academic and community medical centers., Patients: 168 patients in the placebo group of a trial evaluating interferon-gamma1b., Measurements: Measures of physiology and dyspnea assessed at 12-week intervals; hospitalizations; and the pace of deterioration and cause of death over a median period of 76 weeks., Results: Physiologic variables changed minimally during the study. However, 23% of patients required hospitalization for a respiratory disorder and 21% died. Idiopathic pulmonary fibrosis was the primary cause of death in 89% of patients who died, and an apparent acute clinical deterioration preceded death in 47% of these patients., Limitations: The instrument used to define the pace of deterioration and cause of death was applied retrospectively., Conclusions: Recognition of the common occurrence of acute fatal deterioration in patients with mild to moderate IPF has important implications for monitoring patients and supports early referral for lung transplantation.

Background: Idiopathic pulmonary fibrosis is a progressive, fatal disease with no known efficacious therapy., Methods: In a double-blind, multinational trial, we randomly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo., Results: Over a median of 58 weeks, interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival, defined as the time to disease progression or death, and no significant treatment effect was observed on measures of lung function, gas exchange, or the quality of life. Ten percent of patients in the interferon gamma-1b group died, as compared with 17 percent of patients in the placebo group (P=0.08). Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms. However, the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups. More pneumonias were reported among patients in the interferon gamma-1b group, but the incidence of severe or life-threatening respiratory tract infections was similar in the two groups., Conclusions: In a well-defined population of patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or the quality of life. Owing to the size and duration of the trial, a clinically significant survival benefit could not be ruled out., (Copyright 2004 Massachusetts Medical Society)

A correction to the article "Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis," by Tasha E. Fingerlin and colleagues, that was published in a 2013 issue is presented.

Several letters to the editor are presented related to articles published in May 29, 2014 issue including "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis" by Luca Richeldi and "A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis" by Talmadge E. King.