Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene

Blanca E. Himes, Xiaofeng Jiang, Ruoxi Hu, Ann C. Wu, Jessica A. Lasky-Su, Barbara J. Klanderman, John Ziniti, Jody Senter-Sylvia, John J. Lima, Charles G. Irvin, Stephen P. Peters, Deborah A. Meyers, Eugene R. Bleecker, Michiaki Kubo, Mayumi Tamari, Yusuke Nakamura, Stanley J. Szefler, Robert F. Lemanske, Robert S. Zeiger, Robert C. StrunkFernando D. Martinez, John P. Hanrahan, Gerard H. Koppelman, Dirkje S. Postma, Maartje A.E. Nieuwenhuis, Judith M. Vonk, Reynold A. Panettieri, Amy Markezich, Elliot Israel, Vincent J. Carey, Kelan G. Tantisira, Augusto A. Litonjua, Quan Lu, Scott T. Weiss

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere1002824
JournalPLoS Genetics
Volume8
Issue number7
DOIs
Publication statusPublished - 01-07-2012

Fingerprint

bronchodilators
Genome-Wide Association Study
asthma
Bronchodilator Agents
polymorphism
Asthma
genome
gene
genotype
agonists
Genes
single nucleotide polymorphism
genes
Single Nucleotide Polymorphism
adrenergic receptors
phenotype
drug
Adrenergic Receptors
drug therapy
Linear Models

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Himes, B. E., Jiang, X., Hu, R., Wu, A. C., Lasky-Su, J. A., Klanderman, B. J., ... Weiss, S. T. (2012). Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene. PLoS Genetics, 8(7), [e1002824]. https://doi.org/10.1371/journal.pgen.1002824
Himes, Blanca E. ; Jiang, Xiaofeng ; Hu, Ruoxi ; Wu, Ann C. ; Lasky-Su, Jessica A. ; Klanderman, Barbara J. ; Ziniti, John ; Senter-Sylvia, Jody ; Lima, John J. ; Irvin, Charles G. ; Peters, Stephen P. ; Meyers, Deborah A. ; Bleecker, Eugene R. ; Kubo, Michiaki ; Tamari, Mayumi ; Nakamura, Yusuke ; Szefler, Stanley J. ; Lemanske, Robert F. ; Zeiger, Robert S. ; Strunk, Robert C. ; Martinez, Fernando D. ; Hanrahan, John P. ; Koppelman, Gerard H. ; Postma, Dirkje S. ; Nieuwenhuis, Maartje A.E. ; Vonk, Judith M. ; Panettieri, Reynold A. ; Markezich, Amy ; Israel, Elliot ; Carey, Vincent J. ; Tantisira, Kelan G. ; Litonjua, Augusto A. ; Lu, Quan ; Weiss, Scott T. / Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene. In: PLoS Genetics. 2012 ; Vol. 8, No. 7.
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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.",
author = "Himes, {Blanca E.} and Xiaofeng Jiang and Ruoxi Hu and Wu, {Ann C.} and Lasky-Su, {Jessica A.} and Klanderman, {Barbara J.} and John Ziniti and Jody Senter-Sylvia and Lima, {John J.} and Irvin, {Charles G.} and Peters, {Stephen P.} and Meyers, {Deborah A.} and Bleecker, {Eugene R.} and Michiaki Kubo and Mayumi Tamari and Yusuke Nakamura and Szefler, {Stanley J.} and Lemanske, {Robert F.} and Zeiger, {Robert S.} and Strunk, {Robert C.} and Martinez, {Fernando D.} and Hanrahan, {John P.} and Koppelman, {Gerard H.} and Postma, {Dirkje S.} and Nieuwenhuis, {Maartje A.E.} and Vonk, {Judith M.} and Panettieri, {Reynold A.} and Amy Markezich and Elliot Israel and Carey, {Vincent J.} and Tantisira, {Kelan G.} and Litonjua, {Augusto A.} and Quan Lu and Weiss, {Scott T.}",
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Himes, BE, Jiang, X, Hu, R, Wu, AC, Lasky-Su, JA, Klanderman, BJ, Ziniti, J, Senter-Sylvia, J, Lima, JJ, Irvin, CG, Peters, SP, Meyers, DA, Bleecker, ER, Kubo, M, Tamari, M, Nakamura, Y, Szefler, SJ, Lemanske, RF, Zeiger, RS, Strunk, RC, Martinez, FD, Hanrahan, JP, Koppelman, GH, Postma, DS, Nieuwenhuis, MAE, Vonk, JM, Panettieri, RA, Markezich, A, Israel, E, Carey, VJ, Tantisira, KG, Litonjua, AA, Lu, Q & Weiss, ST 2012, 'Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene', PLoS Genetics, vol. 8, no. 7, e1002824. https://doi.org/10.1371/journal.pgen.1002824

Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene. / Himes, Blanca E.; Jiang, Xiaofeng; Hu, Ruoxi; Wu, Ann C.; Lasky-Su, Jessica A.; Klanderman, Barbara J.; Ziniti, John; Senter-Sylvia, Jody; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Meyers, Deborah A.; Bleecker, Eugene R.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Hanrahan, John P.; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A.E.; Vonk, Judith M.; Panettieri, Reynold A.; Markezich, Amy; Israel, Elliot; Carey, Vincent J.; Tantisira, Kelan G.; Litonjua, Augusto A.; Lu, Quan; Weiss, Scott T.

In: PLoS Genetics, Vol. 8, No. 7, e1002824, 01.07.2012.

Research output: Contribution to journalArticle

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.

PY - 2012/7/1

Y1 - 2012/7/1

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