Abstract
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS.
Highlights
Asthma is a chronic respiratory disease that affects over 20 million Americans and 300 million people worldwide [1,2]
We knocked down SPATS2L mRNA in human airway smooth muscle cells and found that b2-adrenergic receptor levels increased, suggesting that SPATS2L may be a regulator of Bronchodilator response (BDR)
A hallmark characteristic of asthma is reversible airway obstruction, which is commonly measured via a bronchodilator response (BDR) test, in which the reduction of bronchoconstriction after administration of a short-acting reliever drug is quantified [3]. b2agonists, the most common short-acting reliever drugs used during BDR tests and for asthma therapy, act in part by stimulating b2adrenergic receptors (b2ARs) on airway smooth muscle cells to reduce bronchoconstriction via subsequent increases in cyclic adenosine monophosphate and protein kinase A (PKA) [3]
Summary
Asthma is a chronic respiratory disease that affects over 20 million Americans and 300 million people worldwide [1,2]. A hallmark characteristic of asthma is reversible airway obstruction, which is commonly measured via a bronchodilator response (BDR) test, in which the reduction of bronchoconstriction after administration of a short-acting reliever drug is quantified [3]. B2agonists, the most common short-acting reliever drugs used during BDR tests and for asthma therapy, act in part by stimulating b2adrenergic receptors (b2ARs) on airway smooth muscle cells to reduce bronchoconstriction via subsequent increases in cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) [3]. In addition to being used for the diagnosis of asthma, BDR tests can be used to measure whether inhaled b2-agonists are effective in patients. Short-acting b2-agonists are widely used clinically as asthma rescue medications, they are variably efficacious among patients [8]. Studying BDR may provide information regarding both the pathophysiology and pharmacogenetics of asthma
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