title: Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Epidemiology, School of Public Health, University of Colorado Denver, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Peljto
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Richards
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Silveira
authors.forename: Kathleen O
authors.initials: KO
authors.lastname: Lindell
authors.forename: Mark P
authors.initials: MP
authors.lastname: Steele
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.forename: Max A
authors.initials: MA
authors.lastname: Seibold
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Janet L
authors.initials: JL
authors.lastname: Talbert
authors.forename: Cheryl
authors.initials: C
authors.lastname: Markin
authors.forename: Karl
authors.initials: K
authors.lastname: Kossen
authors.forename: Scott D
authors.initials: SD
authors.lastname: Seiwert
authors.forename: Elissa
authors.initials: E
authors.lastname: Murphy
authors.forename: Imre
authors.initials: I
authors.lastname: Noth
authors.forename: Marvin I
authors.initials: MI
authors.lastname: Schwarz
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000368:Aged; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D055257:Mucin-5B / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies; D012306:Risk; D016019:Survival Analysis
chemical_list: C524578:MUC5B protein, human; D055257:Mucin-5B