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

Anna L. Peljto, Yingze Zhang, Tasha E. Fingerlin, Ma Shwu-Fan, Joe GN Garcia, Thomas J. Richards, Lori J. Silveira, Kathleen O. Lindell, Mark P. Steele, James E. Loyd, Kevin F. Gibson, Max A. Seibold, Kevin K. Brown, Janet L. Talbert, Cheryl Markin, Karl Kossen, Scott D. Seiwert, Elissa Murphy, Imre Noth, Marvin I. SchwarzNaftali Kaminski, David A. Schwartz

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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 modelin 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, acommonrisk 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.

Original languageEnglish (US)
Pages (from-to)2232-2239
Number of pages8
JournalJournal of the American Medical Association
Volume309
Issue number21
DOIs
StatePublished - 2013
Externally publishedYes

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Idiopathic Pulmonary Fibrosis
Survival
Genotype
Matrix Metalloproteinase 7
Mortality
Molecular Models
Pulmonary Fibrosis
Genetic Models
Interstitial Lung Diseases
Vital Capacity
Carbon Monoxide
Interferons
Canada
Molecular Biology
Retrospective Studies
Alleles
Demography
Outcome Assessment (Health Care)
Clinical Trials

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. / Peljto, Anna L.; Zhang, Yingze; Fingerlin, Tasha E.; Shwu-Fan, Ma; Garcia, Joe GN; Richards, Thomas J.; Silveira, Lori J.; Lindell, Kathleen O.; Steele, Mark P.; Loyd, James E.; Gibson, Kevin F.; Seibold, Max A.; Brown, Kevin K.; Talbert, Janet L.; Markin, Cheryl; Kossen, Karl; Seiwert, Scott D.; Murphy, Elissa; Noth, Imre; Schwarz, Marvin I.; Kaminski, Naftali; Schwartz, David A.

In: Journal of the American Medical Association, Vol. 309, No. 21, 2013, p. 2232-2239.

Research output: Contribution to journalArticle

Peljto, AL, Zhang, Y, Fingerlin, TE, Shwu-Fan, M, Garcia, JGN, Richards, TJ, Silveira, LJ, Lindell, KO, Steele, MP, Loyd, JE, Gibson, KF, Seibold, MA, Brown, KK, Talbert, JL, Markin, C, Kossen, K, Seiwert, SD, Murphy, E, Noth, I, Schwarz, MI, Kaminski, N & Schwartz, DA 2013, 'Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis', Journal of the American Medical Association, vol. 309, no. 21, pp. 2232-2239. https://doi.org/10.1001/jama.2013.5827
Peljto, Anna L. ; Zhang, Yingze ; Fingerlin, Tasha E. ; Shwu-Fan, Ma ; Garcia, Joe GN ; Richards, Thomas J. ; Silveira, Lori J. ; Lindell, Kathleen O. ; Steele, Mark P. ; Loyd, James E. ; Gibson, Kevin F. ; Seibold, Max A. ; Brown, Kevin K. ; Talbert, Janet L. ; Markin, Cheryl ; Kossen, Karl ; Seiwert, Scott D. ; Murphy, Elissa ; Noth, Imre ; Schwarz, Marvin I. ; Kaminski, Naftali ; Schwartz, David A. / Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. In: Journal of the American Medical Association. 2013 ; Vol. 309, No. 21. pp. 2232-2239.
@article{3f437c3de89a46f4afefbaed98adf522,
title = "Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis",
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 modelin 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, acommonrisk 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.",
author = "Peljto, {Anna L.} and Yingze Zhang and Fingerlin, {Tasha E.} and Ma Shwu-Fan and Garcia, {Joe GN} and Richards, {Thomas J.} and Silveira, {Lori J.} and Lindell, {Kathleen O.} and Steele, {Mark P.} and Loyd, {James E.} and Gibson, {Kevin F.} and Seibold, {Max A.} and Brown, {Kevin K.} and Talbert, {Janet L.} and Cheryl Markin and Karl Kossen and Seiwert, {Scott D.} and Elissa Murphy and Imre Noth and Schwarz, {Marvin I.} and Naftali Kaminski and Schwartz, {David A.}",
year = "2013",
doi = "10.1001/jama.2013.5827",
language = "English (US)",
volume = "309",
pages = "2232--2239",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "21",

}

TY - JOUR

T1 - Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis

AU - Peljto, Anna L.

AU - Zhang, Yingze

AU - Fingerlin, Tasha E.

AU - Shwu-Fan, Ma

AU - Garcia, Joe GN

AU - Richards, Thomas J.

AU - Silveira, Lori J.

AU - Lindell, Kathleen O.

AU - Steele, Mark P.

AU - Loyd, James E.

AU - Gibson, Kevin F.

AU - Seibold, Max A.

AU - Brown, Kevin K.

AU - Talbert, Janet L.

AU - Markin, Cheryl

AU - Kossen, Karl

AU - Seiwert, Scott D.

AU - Murphy, Elissa

AU - Noth, Imre

AU - Schwarz, Marvin I.

AU - Kaminski, Naftali

AU - Schwartz, David A.

PY - 2013

Y1 - 2013

N2 - 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 modelin 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, acommonrisk 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.

AB - 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 modelin 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, acommonrisk 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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