Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease.

Saavedra MT, Hughes GJ, Sanders LA, Carr M, Rodman DM, Coldren CD, Geraci MW, Sagel SD, Accurso FJ, West J, Nick JA
Am J Respir Crit Care Med. 2008 178 (9): 929-38

PMID: 18723435 · PMCID: PMC2577728 · DOI:10.1164/rccm.200803-387OC

RATIONALE - Circulating leukocyte RNA transcripts are systemic markers of inflammation, which have not been studied in cystic fibrosis (CF) lung disease. Although the standard assessment of pulmonary treatment response is FEV(1), a measure of airflow limitation, the lack of systemic markers to reflect changes in lung inflammation critically limits the testing of proposed therapeutics.

OBJECTIVES - We sought to prospectively identify and validate peripheral blood leukocyte genes that could mark resolution of pulmonary infection and inflammation using a model by which RNA transcripts could increase the predictive value of spirometry.

METHODS - Peripheral blood mononuclear cells were isolated from 10 patients with CF and acute pulmonary exacerbations before and after therapy. RNA expression profiling revealed that 10 genes significantly changed with treatment when compared with matched non-CF and control subjects with stable CF to establish baseline transcript abundance. Peripheral blood mononuclear cell RNA transcripts were prospectively validated, using real-time polymerase chain reaction amplification, in an independent cohort of acutely ill patients with CF (n = 14). Patients who responded to therapy were analyzed using general estimating equations and multiple logistic regression, such that changes in FEV(1)% predicted were regressed with transcript changes.

MEASUREMENTS AND MAIN RESULTS - Three genes, CD64, ADAM9, and CD36, were significant and independent predictors of a therapeutic response beyond that of FEV(1) alone (P < 0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV(1).

CONCLUSIONS - Circulating mononuclear cell transcripts characterize a response to the treatment of pulmonary exacerbations. Even in small patient cohorts, changes in gene expression in conjunction with FEV(1) may enhance current outcomes measures for treatment response.

MeSH Terms (22)

Acute Disease Adult Anti-Bacterial Agents Biomarkers Cohort Studies Cystic Fibrosis Cytokines Female Forced Expiratory Volume Gene Expression Profiling Humans Leukocytes Male Oligonucleotide Array Sequence Analysis Predictive Value of Tests Prospective Studies Reproducibility of Results Reverse Transcriptase Polymerase Chain Reaction RNA Precursors ROC Curve Spirometry Young Adult

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