Article

Idiopathic pulmonary fibrosis: new evidence and an improved standard of care in 2012

Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, University of Washington, Seattle, WA 98195, USA.
The Lancet (Impact Factor: 45.22). 08/2012; 380(9842):699-701. DOI: 10.1016/S0140-6736(12)61256-2
Source: PubMed
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    ABSTRACT: 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 1.1 × 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.
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    ABSTRACT: A r t i c l e s IIPs represent a group of lung diseases commonly characterized by pulmonary fibrosis or progressive scarring of the alveolar intersti-tium that can lead to significant morbidity and mortality due to hypoxemic respiratory insufficiency 1 . Although some forms of pul-monary fibrosis are associated with known environmental expo-sures (for example, asbestos), drug toxicity 2 , radiation exposure or collagen vascular diseases (for example, scleroderma), IIPs have no known etiology. The most common and severe IIP is idiopathic pulmonary fibrosis (IPF) 1 , which has a median survival time of 2–3 years after diagnosis. There are no IPF pharmacological thera-pies approved for use in the United States, and lung transplantation is the only intervention known to prolong life 3 . Although all IIPs have a variable clinical course, they often progress to end-stage lung disease and death. It seems likely that risk of IIP is determined by multiple genetic variants and environmental toxins, but the specific causes of IIP are only beginning to emerge. The evidence for a genetic component to the risk of IIP is substan-tial and includes familial clustering of disease, the occurrence of pul-monary fibrosis as part of systemic genetic syndromes, considerable variability in the risk of pulmonary fibrosis among those with similar exposures to known environmental agents, such as asbestos, and the identification of genetic risk loci for IIP. Rare mutations in the TERT, TERC, SFTPC and SFTPA2 genes have been associated with familial interstitial pneumonia (FIP; defined as two or more family members with IIP) and IPF 4–9 , and a common polymorphism in TERT has been associated with IPF 10 . Recently, we identified a promoter vari-ant in the MUC5B gene (rs35705950) that is present in approximately 50–60% of individuals with FIP or IPF and is estimated to increase risk by 6-fold for heterozygotes and by 20-fold for homozygotes 11 . The identification of MUC5B as a common risk factor has altered our view of the pathogenesis of pulmonary fibrosis from focusing primarily on alveolar epithelia and the lung matrix to inclusion of Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis
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    ABSTRACT: 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. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of survival in 2 independent cohorts of patients with IPF: the INSPIRE cohort, consisting of patients enrolled in the interferon-γ1b trial (n = 438; December 15, 2003-May 2, 2009; 81 centers in 7 European countries, the United States, and Canada), and the Chicago cohort, consisting of IPF participants recruited from the Interstitial Lung Disease Clinic at the University of Chicago (n = 148; 2007-2010). The INSPIRE cohort was used to model the association of the MUC5B genotype with survival, accounting for the effect of matrix metalloproteinase 7 (MMP-7) blood concentration and other demographic and clinical covariates. The Chicago cohort was used for replication of findings. MAIN OUTCOMES AND MEASURES The primary end point was all-cause mortality. RESULTS The numbers of patients in the GG, GT, and TT genotype groups were 148 (34%), 259 (59%), and 31 (7%), respectively, in the INSPIRE cohort and 41 (28%), 98 (66%), and 9 (6%), respectively, in the Chicago cohort. The median follow-up period was 1.6 years for INSPIRE and 2.1 years for Chicago. During follow-up, there were 73 deaths (36 GG, 35 GT, and 2 TT) among INSPIRE patients and 64 deaths (26 GG, 36 GT, and 2 TT) among Chicago patients. The unadjusted 2-year cumulative incidence of death was lower among patients carrying 1 or more copies of the IPF risk allele (T) in both the INSPIRE cohort (0.25 [95% CI, 0.17-0.32] for GG, 0.17 [95% CI, 0.11-0.23] for GT, and 0.03 [95% CI, 0.00-0.09] for TT) and the Chicago cohort (0.50 [95% CI, 0.31-0.63] for GG, 0.22 [95% CI, 0.13-0.31] for GT, and 0.11 [95% CI, 0.00-0.28] for TT). In the INSPIRE cohort, the TT and GT genotypes (risk for IPF) were associated with improved survival compared with GG (hazard ratios, 0.23 [95% CI, 0.10-0.52] and 0.48 [95% CI, 0.31-0.72], respectively; P < .001). This finding was replicated in the Chicago cohort (hazard ratios, 0.15 [95% CI, 0.05-0.49] and 0.39 [95% CI, 0.21-0.70], respectively; P < .002). The observed association of MUC5B with survival was independent of age, sex, forced vital capacity, diffusing capacity of carbon monoxide, MMP-7, and treatment status. The addition of the MUC5B genotype to the survival models significantly improved the predictive accuracy of the model in both the INSPIRE cohort (C = 0.71 [95% CI, 0.64-0.75] vs C = 0.68 [95% CI, 0.61-0.73]; P < .001) and the Chicago cohort (C = 0.73 [95% CI, 0.62-0.78] vs C = 0.69 [95% CI, 0.59-0.75]; P = .01). CONCLUSIONS AND RELEVANCE Among patients with IPF, a common risk polymorphism in MUC5B was significantly associated with improved survival. Further research is necessary to refine the risk estimates and to determine the clinical implications of these findings.
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