TY - JOUR
T1 - P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy
AU - Denlinger, Loren C.
AU - Manthei, David M.
AU - Seibold, Max A.
AU - Ahn, Kwangmi
AU - Bleecker, Eugene
AU - Boushey, Homer A.
AU - Calhoun, William J.
AU - Castro, Mario
AU - Chinchili, Vernon M.
AU - Fahy, John V.
AU - Hawkins, Greg A.
AU - Icitovic, Nicolina
AU - Israel, Elliot
AU - Jarjour, Nizar N.
AU - King, Tonya
AU - Kraft, Monica
AU - Lazarus, Stephen C.
AU - Lehman, Erik
AU - Martin, Richard J.
AU - Meyers, Deborah A.
AU - Peters, Stephen P.
AU - Sheerar, Dagna
AU - Shi, Lei
AU - Sutherland, E. Rand
AU - Szefler, Stanley J.
AU - Wechsler, Michael E.
AU - Sorkness, Christine A.
AU - Lemanske, Robert F.
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
KW - Asthma
KW - Asthma Clinical Research Network
KW - Corticosteroids
KW - Exacerbation
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U2 - 10.1164/rccm.201204-0750OC
DO - 10.1164/rccm.201204-0750OC
M3 - Article
C2 - 23144325
AN - SCOPUS:84872003277
SN - 1073-449X
VL - 187
SP - 28
EP - 33
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 1
ER -