SummaryBackground-Combined long-acting β 2 -agonist and inhaled corticosteroid (LABA/ICS) therapy improves outcomes in many asthmatics. Some studies suggest that patients homozygous for arginine at the 16 th amino-acid position of the β 2 adrenergic receptor (B16 Arg/Arg) benefit less than those with B16 Gly/Gly.

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.

Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci. Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma. Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV 1 in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma. Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 3 10 26. Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 3 10 25 for rs3127412 and 6.13 3 10 26 for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV 1 response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP. Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.Keywords: polymorphism; genome; pharmacogenomics; glucocorticoid Approximately 300 million individuals worldwide carry a diagnosis of asthma (1). Asthma is a genetic disease, known for more than three centuries to cluster in families. Based on twin studies, the broad sense heritability estimates (proportion of the total variance of a trait due to genetic causes) of an asthma diagnosis range from approximately 36-75%. For asthma control, the most widely prescribed medications are inhaled corticosteroids (ICS). Endogenous corticosteroid level and exogenous therapeutic Supported by NIH U01 HL65899 and R01 HL092197. SHARP was funded by NIH U10 HL74231, U01 HL65899, U54LM8748, U01 HL75232, U01 HL75408, U01 HL75409, U01 HL75415, U01 HL75416, U01 HL75417, U01 HL75419, U01 HL75420, U10 HL64287, U10 HL64288, U10 HL64295, U10 HL64305, U10 HL64307, U01 HL64313, U10 HL51831, U10 HL51834, U10 HL51843, U10 HL51810, U10 HL51823, U10 HL51845, and U10 HL56443. The full SHARP acknowledgment can be found in the online supplement. The NHLBI SHARe (SNP Health Association Resource) genotyping services were provided by Affymetrix, Inc. under US Federal Government contract number N02-HL-6-4278 from the NHLBI. The NIH GWAS Repository of ...