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

Abstract

RATIONALE:

The function of the P2X(7) 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 P2X(7), asthma exacerbations, and incomplete symptom control 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 P2X(7) 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 β(2)-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 FEV(1) reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase.

CONCLUSIONS:

P2X(7) pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.

• Authors: 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 Meyers, Stephen P Peters, Dagna Sheerar, Lei Shi, E Rand Sutherland, Stanley J Szefler, Michael E Wechsler, Christine A Sorkness, Robert F Lemanske Jr, NHLBI Asthma Clinical Research Network Investigators
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 187 Issue 1 Pg. 28-33 (Jan 01 2013) ISSN: 1535-4970 [Electronic] United States
• PMID: 23144325 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adrenal Cortex Hormones
• P2RX7 protein, human
• Receptors, Purinergic P2X7
• Albuterol
• Prednisone

Topics

• Adrenal Cortex Hormones (administration & dosage)
• Adult
• Black or African American (genetics)
• Albuterol (administration & dosage)
• Asthma (genetics, immunology, physiopathology, therapy)
• Case-Control Studies
• Disease Progression
• Female
• Forced Expiratory Volume
• Humans
• Male
• Nuclear Pore (immunology)
• Polymorphism, Single Nucleotide
• Prednisone (administration & dosage)
• Receptors, Purinergic P2X7 (genetics, immunology, physiology)