TY - JOUR
T1 - Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene
AU - Himes, Blanca E.
AU - Jiang, Xiaofeng
AU - Hu, Ruoxi
AU - Wu, Ann C.
AU - Lasky-Su, Jessica A.
AU - Klanderman, Barbara J.
AU - Ziniti, John
AU - Senter-Sylvia, Jody
AU - Lima, John J.
AU - Irvin, Charles G.
AU - Peters, Stephen P.
AU - Meyers, Deborah A.
AU - Bleecker, Eugene R.
AU - Kubo, Michiaki
AU - Tamari, Mayumi
AU - Nakamura, Yusuke
AU - Szefler, Stanley J.
AU - Lemanske, Robert F.
AU - Zeiger, Robert S.
AU - Strunk, Robert C.
AU - Martinez, Fernando D.
AU - Hanrahan, John P.
AU - Koppelman, Gerard H.
AU - Postma, Dirkje S.
AU - Nieuwenhuis, Maartje A.E.
AU - Vonk, Judith M.
AU - Panettieri, Reynold A.
AU - Markezich, Amy
AU - Israel, Elliot
AU - Carey, Vincent J.
AU - Tantisira, Kelan G.
AU - Litonjua, Augusto A.
AU - Lu, Quan
AU - Weiss, Scott T.
N1 - Funding Information:
We thank all CAMP subjects for their ongoing participation in this study. We acknowledge the CAMP investigators and research team, supported by the National Heart, Lung, and Blood Institute (NHLBI), for collection of CAMP Genetic Ancillary Study data. All work on data collected from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women's Hospital under appropriate CAMP policies and human subject's protections. We thank the American Lung Association Asthma Clinical Research Centers (ALA-ACRC) for use of LOCCS and LODO study samples.
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1002824
DO - 10.1371/journal.pgen.1002824
M3 - Article
C2 - 22792082
AN - SCOPUS:84864587259
SN - 1553-7390
VL - 8
JO - PLoS Genetics
JF - PLoS Genetics
IS - 7
M1 - e1002824
ER -
