P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy

Loren C. Denlinger, David M. Manthei, Max A. Seibold, Kwangmi Ahn, Eugene Bleecker, Homer A. Boushey, William J. Calhoun, Mario Castro, Vernon M. Chinchili, John V. Fahy, Greg A. Hawkins, Nicolina Icitovic, Elliot Israel, Nizar N. Jarjour, Tonya King, Monica Kraft, Stephen C. Lazarus, Erik Lehman, Richard J. Martin, Deborah A. MeyersStephen P. Peters, Dagna Sheerar, Lei Shi, E. Rand Sutherland, Stanley J. Szefler, Michael E. Wechsler, Christine A. Sorkness, Robert F. Lemanske

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Rationale: The function of the P2X7 nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied. Objectives: To evaluate the association between P2X7, asthma exacerbations, and incomplete symptomc ontrol in a more diverse population. Methods: A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X7 pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently. Measurements and Main Results: A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β2-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2-6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1-9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV1 reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase. Conclusions: P2X7 pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.

Original languageEnglish (US)
Pages (from-to)28-33
Number of pages6
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume187
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Asthma
  • Asthma Clinical Research Network
  • Corticosteroids
  • Exacerbation
  • P2X

ASJC Scopus subject areas

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

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    Denlinger, L. C., Manthei, D. M., Seibold, M. A., Ahn, K., Bleecker, E., Boushey, H. A., Calhoun, W. J., Castro, M., Chinchili, V. M., Fahy, J. V., Hawkins, G. A., Icitovic, N., Israel, E., Jarjour, N. N., King, T., Kraft, M., Lazarus, S. C., Lehman, E., Martin, R. J., ... Lemanske, R. F. (2013). P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy. American Journal of Respiratory and Critical Care Medicine, 187(1), 28-33. https://doi.org/10.1164/rccm.201204-0750OC