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Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias.
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- Additional Information
- Source:
Publisher: BioMed Central Country of Publication: England NLM ID: 100965258 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2164 (Electronic) Linking ISSN: 14712164 NLM ISO Abbreviation: BMC Genomics Subsets: MEDLINE
- Publication Information:
Original Publication: London : BioMed Central, [2000-
- Subject Terms:
- Abstract:
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 DLCO) 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 DLCO, 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.
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- Grant Information:
RC2 HL101715 United States HL NHLBI NIH HHS; HL121572 United States HL NHLBI NIH HHS; HL097163 United States HL NHLBI NIH HHS; HL099571 United States HL NHLBI NIH HHS; R01 HL080396 United States HL NHLBI NIH HHS; RC1 HL099571 United States HL NHLBI NIH HHS; HL101715 United States HL NHLBI NIH HHS; R21 HL121572 United States HL NHLBI NIH HHS; R01 HL097163 United States HL NHLBI NIH HHS; R01 HL095393 United States HL NHLBI NIH HHS; R33 HL120770 United States HL NHLBI NIH HHS; HL095393 United States HL NHLBI NIH HHS
- Accession Number:
0 (E-Selectin)
0 (HIF1A protein, human)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (Intracellular Signaling Peptides and Proteins)
0 (Proteins)
0 (RTKN2 protein, human)
0 (Receptor for Advanced Glycation End Products)
0 (SELE protein, human)
0 (SERPINA3 protein, human)
0 (SERPINE2 protein, human)
0 (Serpin E2)
0 (Serpins)
EC 3.4.24.- (ADAM Proteins)
EC 3.4.24.- (ADAMTS9 Protein)
EC 3.4.24.- (ADAMTS9 protein, human)
EC 3.4.24.14 (Procollagen N-Endopeptidase)
EC 3.4.24.82 (ADAMTS4 Protein)
EC 3.4.24.82 (ADAMTS4 protein, human)
- Publication Date:
Date Created: 20151028 Date Completed: 20160721 Latest Revision: 20191204
- Publication Date:
20221213
- Accession Number:
PMC4621862
- Accession Number:
10.1186/s12864-015-2102-3
- Accession Number:
26503507
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