Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease

Milene T. Saavedra, Grant J. Hughes, Linda A. Sanders, Michelle Carr, David M. Rodman, Christopher D. Coldren, Mark W. Geraci, Scott D. Sagel, Frank J. Accurso, James West, Jerry A. Nick

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 FEV1% 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 FEV1 alone (P <0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV1. 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 FEV1 may enhance current outcomes measures for treatment response.

Original languageEnglish (US)
Pages (from-to)929-938
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume178
Issue number9
DOIs
StatePublished - Nov 1 2008
Externally publishedYes

Fingerprint

Cystic Fibrosis
Lung Diseases
RNA
Therapeutics
Genes
Blood Cells
Pneumonia
Leukocytes
Lung
Spirometry
ROC Curve
Real-Time Polymerase Chain Reaction
Fibrosis
Logistic Models
Outcome Assessment (Health Care)
Inflammation
Gene Expression
Infection

Keywords

  • Biomarkers
  • Cystic fibrosis
  • Peripheral blood mononuclear cells
  • Pulmonary exacerbation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Saavedra, M. T., Hughes, G. J., Sanders, L. A., Carr, M., Rodman, D. M., Coldren, C. D., ... Nick, J. A. (2008). Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease. American Journal of Respiratory and Critical Care Medicine, 178(9), 929-938. https://doi.org/10.1164/rccm.200803-387OC

Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease. / Saavedra, Milene T.; Hughes, Grant J.; Sanders, Linda A.; Carr, Michelle; Rodman, David M.; Coldren, Christopher D.; Geraci, Mark W.; Sagel, Scott D.; Accurso, Frank J.; West, James; Nick, Jerry A.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 178, No. 9, 01.11.2008, p. 929-938.

Research output: Contribution to journalArticle

Saavedra, MT, Hughes, GJ, Sanders, LA, Carr, M, Rodman, DM, Coldren, CD, Geraci, MW, Sagel, SD, Accurso, FJ, West, J & Nick, JA 2008, 'Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease', American Journal of Respiratory and Critical Care Medicine, vol. 178, no. 9, pp. 929-938. https://doi.org/10.1164/rccm.200803-387OC
Saavedra, Milene T. ; Hughes, Grant J. ; Sanders, Linda A. ; Carr, Michelle ; Rodman, David M. ; Coldren, Christopher D. ; Geraci, Mark W. ; Sagel, Scott D. ; Accurso, Frank J. ; West, James ; Nick, Jerry A. / Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease. In: American Journal of Respiratory and Critical Care Medicine. 2008 ; Vol. 178, No. 9. pp. 929-938.
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abstract = "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 FEV1{\%} 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 FEV1 alone (P <0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV1. 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 FEV1 may enhance current outcomes measures for treatment response.",
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AU - Sanders, Linda A.

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AU - Rodman, David M.

AU - Coldren, Christopher D.

AU - Geraci, Mark W.

AU - Sagel, Scott D.

AU - Accurso, Frank J.

AU - West, James

AU - Nick, Jerry A.

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N2 - 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 FEV1% 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 FEV1 alone (P <0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV1. 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 FEV1 may enhance current outcomes measures for treatment response.

AB - 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 FEV1% 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 FEV1 alone (P <0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV1. 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 FEV1 may enhance current outcomes measures for treatment response.

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