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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 b...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621862/ https://www.ncbi.nlm.nih.gov/pubmed/26503507 http://dx.doi.org/10.1186/s12864-015-2102-3 |
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author | Steele, Mark P. Luna, Leah G. Coldren, Christopher D. Murphy, Elissa Hennessy, Corinne E. Heinz, David Evans, Christopher M. Groshong, Steve Cool, Carlyne Cosgrove, Gregory P. Brown, Kevin K. Fingerlin, Tasha E. Schwarz, Marvin I. Schwartz, David A. Yang, Ivana V. |
author_facet | Steele, Mark P. Luna, Leah G. Coldren, Christopher D. Murphy, Elissa Hennessy, Corinne E. Heinz, David Evans, Christopher M. Groshong, Steve Cool, Carlyne Cosgrove, Gregory P. Brown, Kevin K. Fingerlin, Tasha E. Schwarz, Marvin I. Schwartz, David A. Yang, Ivana V. |
author_sort | Steele, Mark P. |
collection | PubMed |
description | 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 D(L)CO) 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. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples. CONCLUSIONS: We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and D(L)CO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2102-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4621862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-46218622015-10-28 Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias Steele, Mark P. Luna, Leah G. Coldren, Christopher D. Murphy, Elissa Hennessy, Corinne E. Heinz, David Evans, Christopher M. Groshong, Steve Cool, Carlyne Cosgrove, Gregory P. Brown, Kevin K. Fingerlin, Tasha E. Schwarz, Marvin I. Schwartz, David A. Yang, Ivana V. BMC Genomics Research Article 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 D(L)CO) 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. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1α, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples. CONCLUSIONS: We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and D(L)CO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2102-3) contains supplementary material, which is available to authorized users. BioMed Central 2015-10-26 /pmc/articles/PMC4621862/ /pubmed/26503507 http://dx.doi.org/10.1186/s12864-015-2102-3 Text en © Steele et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Steele, Mark P. Luna, Leah G. Coldren, Christopher D. Murphy, Elissa Hennessy, Corinne E. Heinz, David Evans, Christopher M. Groshong, Steve Cool, Carlyne Cosgrove, Gregory P. Brown, Kevin K. Fingerlin, Tasha E. Schwarz, Marvin I. Schwartz, David A. Yang, Ivana V. Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias |
title | Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias |
title_full | Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias |
title_fullStr | Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias |
title_full_unstemmed | Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias |
title_short | Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias |
title_sort | relationship between gene expression and lung function in idiopathic interstitial pneumonias |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621862/ https://www.ncbi.nlm.nih.gov/pubmed/26503507 http://dx.doi.org/10.1186/s12864-015-2102-3 |
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