Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis.

TitlePeripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis.
Publication TypeJournal Article
Year of Publication2013
AuthorsHerazo-Maya JD, Noth I, Duncan SR, Kim S, Ma S-F, Tseng GC, Feingold E, Juan-Guardela BM, Richards TJ, Lussier Y, Huang Y, Vij R, Lindell KO, Xue J, Gibson KF, Shapiro SD, Garcia JGN, Kaminski N
JournalSci Transl Med
Volume5
Issue205
Pagination205ra136
Date Published2013 Oct 02
ISSN Number1946-6242
KeywordsAntigens, CD28, Antigens, CD4, Biomarkers, Cluster Analysis, Cohort Studies, Gene Expression Profiling, Humans, Idiopathic Pulmonary Fibrosis, Leukocytes, Mononuclear, Oligonucleotide Array Sequence Analysis, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Treatment Outcome
Abstract

<p>We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. We studied the pathways associated with TFS in each independent microarray cohort and identified decreased expression of "The costimulatory signal during T cell activation" Biocarta pathway and, in particular, the genes CD28, ICOS, LCK, and ITK, results confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient's age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4(+)CD28(+) T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.</p>

DOI10.1126/scitranslmed.3005964
Alternate JournalSci Transl Med
PubMed ID24089408
PubMed Central IDPMC4175518
Grant ListU01 HL105371 / HL / NHLBI NIH HHS / United States
UL1 TR000005 / TR / NCATS NIH HHS / United States
HL073241 / HL / NHLBI NIH HHS / United States
RC2 HL101740 / HL / NHLBI NIH HHS / United States
HL0894932 / HL / NHLBI NIH HHS / United States
HL108642 / HL / NHLBI NIH HHS / United States
U10 HL080513 / HL / NHLBI NIH HHS / United States
P50 HL107172 / HL / NHLBI NIH HHS / United States
HL080513 / HL / NHLBI NIH HHS / United States
U01 HL108642 / HL / NHLBI NIH HHS / United States
R01 HL095397 / HL / NHLBI NIH HHS / United States
HL101740 / HL / NHLBI NIH HHS / United States
HL107172 / HL / NHLBI NIH HHS / United States
HL105371 / HL / NHLBI NIH HHS / United States
HL095397 / HL / NHLBI NIH HHS / United States
P50 HL084932 / HL / NHLBI NIH HHS / United States
R01 HL073241 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
HL98050 / HL / NHLBI NIH HHS / United States