Attenuated P2X7 pore function as a risk factor for virus-induced loss of asthma control.
BACKGROUND
Upper respiratory tract infection is a guideline accepted risk domain for the loss of asthma control. The ionotrophic nucleotide receptor P2X(7) regulates compartmentalized acute inflammation and the immune response to airway pathogens.


OBJECTIVE
We hypothesized that variability in P2X(7) function contributes to neutrophilic airway inflammation during a cold and thereby is linked to acute asthma.


METHODS
Research volunteers with asthma were enrolled at the onset of a naturally occurring cold and monitored through convalescence, assessing symptoms, lung function, and airway inflammation. P2X(7) pore activity in whole blood samples was measured using a genomically validated flow cytometric assay.


RESULTS
Thirty-five participants with mild to moderate allergic asthma were enrolled and 31 completed all visits. P2X(7) pore function correlated with the change in nasal lavage neutrophil counts during the cold (R(s) = 0.514, P = 0.004) and was inversely related to the change in asthma symptoms (R(s) = -0.486, P = 0.009). The change in peak expiratory flow recordings, precold use of inhaled corticosteroids, and P2X(7) pore function were multivariate predictors of asthma symptoms (P = 0.001, < 0.001 and = 0.003 respectively). Attenuated P2X(7) activity was associated with the risk of losing asthma control (crude odds ratio, 11.0; 95% confidence interval, 1.1-106.4) even after adjustment for inhaled corticosteroids and rhinovirus (odds ratio, 15.0).


CONCLUSIONS
A whole blood P2X(7) pore assay robustly identifies participants with loss-of-function genotypes. Using this assay as an epidemiologic tool, attenuated P2X(7) pore activity may be a novel biomarker of virus-induced loss of asthma control.
Denlinger
Loren C
LC
Section of Allergy, Pulmonary, and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, P.O. Box 9988, Madison, WI 53792, USA. ldenling@wisc.edu
Shi
Lei
L
Guadarrama
Arturo
A
Schell
Kathy
K
Green
Dawn
D
Morrin
Alison
A
Hogan
Kirk
K
Sorkness
Ronald L
RL
Busse
William W
WW
Gern
James E
JE
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D000420:Albuterol / Q000008:administration & dosage; D001249:Asthma / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D001991:Bronchitis / Q000276:immunology / Q000821:virology; D001993:Bronchodilator Agents / Q000008:administration & dosage; D003139:Common Cold / Q000276:immunology / Q000821:virology*; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D015640:Ion Channel Gating / Q000276:immunology*; D017817:Nasal Lavage Fluid / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D022022:Nuclear Pore / Q000276:immunology; D016017:Odds Ratio; D010366:Peak Expiratory Flow Rate / Q000276:immunology; D018048:Receptors, Purinergic P2 / Q000097:blood / Q000276:immunology*; D058486:Receptors, Purinergic P2X7; D012307:Risk Factors; D014777:Virus Diseases / Q000150:complications*
D000305:Adrenal Cortex Hormones; D015415:Biomarkers; D001993:Bronchodilator Agents; C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000420:Albuterol