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 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.
Department of Medicine, Vanderbilt University, Nashville, TN, USA.
Mark P
MP
Steele
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
Leah G
LG
Luna
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Christopher D
CD
Coldren
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Elissa
E
Murphy
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Corinne E
CE
Hennessy
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
David
D
Heinz
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Christopher M
CM
Evans
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.|Department of Medicine, National Jewish Health, Denver, CO, USA.
Steve
S
Groshong
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.|Department of Medicine, National Jewish Health, Denver, CO, USA.
Carlyne
C
Cool
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.|Department of Medicine, National Jewish Health, Denver, CO, USA.
Gregory P
GP
Cosgrove
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.|Department of Medicine, National Jewish Health, Denver, CO, USA.
Kevin K
KK
Brown
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.|Department of Biostatistics and Bioinformatics, Colorado School of Public Health, Aurora, CO, USA.
Tasha E
TE
Fingerlin
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Marvin I
MI
Schwarz
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.|Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.|Department of Medicine, National Jewish Health, Denver, CO, USA.
David A
DA
Schwartz
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA. ivana.yang@ucdenver.edu.|Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA. ivana.yang@ucdenver.edu.|Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA. ivana.yang@ucdenver.edu.
Ivana V
IV
Yang
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000071119:ADAMTS9 Protein; D000328:Adult; D000368:Aged; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D054988:Idiopathic Interstitial Pneumonias / Q000235:genetics* / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism
D019040:E-Selectin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C495970:RTKN2 protein, human; D000067759:Receptor for Advanced Glycation End Products; C546936:SELE protein, human; C516148:SERPINA3 protein, human; C545486:SERPINE2 protein, human; D058258:Serpin E2; D015843:Serpins; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human