Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response.
BACKGROUND
Recent findings have raised new interests about the use of anticholinergics, especially tiotropium, for the treatment of asthma. This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics, and to identify factors capable of predicting the response to tiotropium, using a pharmacogenetic approach.


METHODS
A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited. Tiotropium 18 microg was added once a day and lung functions were measured every 4 weeks. Responders were defined as those with an improvement of > or = 15% (or 200 ml) in the forced expiratory volume in 1 s (FEV1) that was maintained for at least 8 successive weeks. Eleven single nucleotide polymorphisms (SNPs) in CHRM1-3 (coding muscarinic receptors one to three) which were identified by re-sequencing, and Arg16Gly and Gln27Glu in ADRB2 (coding beta(2) adrenoreceptor) were scored in 80 of the 138 asthmatics.


RESULTS
Forty-six of the 138 asthmatics (33.3%) responded to tiotropium treatment. Logistic regression analyses (controlled for age, gender, and smoking status) showed that Arg16Gly in ADRB2 [P = 0.003, OR (95% CI) = 0.21 (0.07-0.59) in a minor allele-dominant model] was significantly associated with response to tiotropium.


CONCLUSIONS
As many as 30% of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium. The presence of Arg16Gly in ADRB2 may predict response to tiotropium.
Park
H-W
HW
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Yang
M-S
MS
Park
C-S
CS
Kim
T-B
TB
Moon
H-B
HB
Min
K-U
KU
Kim
Y-Y
YY
Cho
S-H
SH
D000368:Aged; D000483:Alleles; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D043643:Receptor, Muscarinic M1; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000276:immunology; D011976:Receptors, Muscarinic / Q000235:genetics* / Q000276:immunology; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000627:therapeutic use*; D000069447:Tiotropium Bromide
D001993:Bronchodilator Agents; C086088:CHRM1 protein, human; D043643:Receptor, Muscarinic M1; D018343:Receptors, Adrenergic, beta-2; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide