Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV(1)) before and after the administration of a short-acting β(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β(2)-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 FEV(1) after administration of a β(2)-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 β(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β(2)-agonists through GWAS.
Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. blanca.himes@channing.harvard.edu
Blanca E
BE
Himes
Xiaofeng
X
Jiang
Ruoxi
R
Hu
Ann C
AC
Wu
Jessica A
JA
Lasky-Su
Barbara J
BJ
Klanderman
John
J
Ziniti
Jody
J
Senter-Sylvia
John J
JJ
Lima
Charles G
CG
Irvin
Stephen P
SP
Peters
Deborah A
DA
Meyers
Eugene R
ER
Bleecker
Michiaki
M
Kubo
Mayumi
M
Tamari
Yusuke
Y
Nakamura
Stanley J
SJ
Szefler
Robert F
RF
Lemanske
Robert S
RS
Zeiger
Robert C
RC
Strunk
Fernando D
FD
Martinez
John P
JP
Hanrahan
Gerard H
GH
Koppelman
Dirkje S
DS
Postma
Maartje A E
MA
Nieuwenhuis
Judith M
JM
Vonk
Reynold A
RA
Panettieri
Amy
A
Markezich
Elliot
E
Israel
Vincent J
VJ
Carey
Kelan G
KG
Tantisira
Augusto A
AA
Litonjua
Quan
Q
Lu
Scott T
ST
Weiss
D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000402:Airway Obstruction / Q000473:pathology; D001249:Asthma / Q000188:drug therapy / Q000235:genetics*; D054316:Biomarkers, Pharmacological; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*
D058666:Adrenergic beta-2 Receptor Agonists; D054316:Biomarkers, Pharmacological; D001993:Bronchodilator Agents; D011506:Proteins; C486737:SPATS2 protein, human