Abstract
Short-acting b2-adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. The aim of this study was to test whether genetic variants in PDE4D gene, a key regulator of b2-adrenoceptor-induced cAMP turnover in airway smooth muscle cells, affect the response to short-acting b2-agonists. Bronchodilator responsiveness was assessed in 133 asthmatic children by % change in baseline forced expiratory volume in one second (FEV1) after administration of albuterol. The analyses were performed in patients with airway obstruction (FEV1/FVC ratio below 90%, n = 93). FEV1 % change adjusted for baseline FEV1 values was significantly different between genotypes of rs1544791 G/A polymorphism (P = 0.006) and −1345 C/T (rs1504982) promoter variation (P = 0.03). The association remained significant with inclusion of age, sex, atopy, and controller medication into multivariate model (P = 0.004 and P = 0.02, resp.). Our work identifies new genetic variants implicated in modulation of asthma treatment, one of them (rs1544791) previously associated with asthma phenotype.
Highlights
Asthma (MIM 600807) is a common chronic respiratory disease resulting from the complex interaction of genetics and environmental factors [1]
Long PDE4D5 isoform was shown to be a key regulator of b2-adrenoceptor-induced cyclic adenosine monophosphate (cAMP) turnover in human airway smooth muscle cells [11]
Asthma severity of patients recruited in our study is comparable to that observed in the Childhood Asthma Management Program (CAMP) and the Leukotriene Modifier or Corticosteroid or Corticosteroid Salmeterol trial (LOCCS) populations [35] used in a number of pharmacogenetic studies
Summary
Asthma (MIM 600807) is a common chronic respiratory disease resulting from the complex interaction of genetics and environmental factors [1]. CAMP-activated PKA activates and phosphorylates phosphodiesterase 4 (PDE4) isoforms which degrade cAMP providing a pivotal acute feedback mechanism [2,3,4]. Four genes (4A–D) encode a large number of PDE4 isoforms through activation of different promoters or alternative splicing [3, 7]. The dominant PDE4 type expressed in airway smooth muscle cells is PDE4D [8,9,10]. Long PDE4D5 isoform was shown to be a key regulator of b2-adrenoceptor-induced cAMP turnover in human airway smooth muscle cells [11]. The promoter of PDE4D5 isoform contains a cAMP response element [8].
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