Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene

被引：93

作者：

Himes, Blanca E. ^{[1
,2
,3
]}

Jiang, Xiaofeng ^{[4
]}

Hu, Ruoxi ^{[4
]}

Wu, Ann C. ^{[5
]}

Lasky-Su, Jessica A. ^{[1
]}

Klanderman, Barbara J. ^{[2
]}

Ziniti, John ^{[1
]}

Senter-Sylvia, Jody ^{[1
]}

Lima, John J. ^{[6
]}

Irvin, Charles G. ^{[7
]}

Peters, Stephen P. ^{[8
]}

Meyers, Deborah A. ^{[8
]}

Bleecker, Eugene R. ^{[8
]}

Kubo, Michiaki

Tamari, Mayumi

Nakamura, Yusuke ^{[9
]}

Szefler, Stanley J. ^{[10
,11
]}

Lemanske, Robert F., Jr. ^{[12
]}

Zeiger, Robert S. ^{[14
]}

Strunk, Robert C. ^{[13
]}

Martinez, Fernando D. ^{[15
]}

Hanrahan, John P. ^{[16
]}

Koppelman, Gerard H. ^{[17
]}

Postma, Dirkje S. ^{[18
]}

Nieuwenhuis, Maartje A. E. ^{[18
]}

Vonk, Judith M. ^{[19
]}

Panettieri, Reynold A., Jr. ^{[20
]}

Markezich, Amy ^{[21
]}

Israel, Elliot ^{[22
]}

Carey, Vincent J. ^{[1
]}

Tantisira, Kelan G. ^{[1
]}

Litonjua, Augusto A. ^{[1
]}

Lu, Quan ^{[4
]}

Weiss, Scott T. ^{[1
,2
]}

机构：

[1] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA

[3] Childrens Hosp Informat Program, Boston, MA USA

[4] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Program Mol & Integrat Physiol Sci, Boston, MA 02115 USA

[5] Harvard Pilgrim Hlth Care, Dept Populat Med, Boston, MA USA

[6] Ctr Pharmacogen & Translat Res, Nemours Childrens Clin, Jacksonville, FL USA

[7] Univ Vermont, Vermont Lung Ctr, Dept Physiol & Med, Burlington, VT USA

[8] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA

[9] Univ Tokyo, Inst Med Sci, Mol Med Lab, Tokyo, Japan

[10] Univ Colorado, Denver Sch Med, Denver, CO 80202 USA

[11] Natl Jewish Hlth, Denver, CO USA

[12] Univ Wisconsin, Ctr Clin Sci, Madison, WI USA

[13] Washington Univ, Sch Med, St Louis, MO USA

[14] Kaiser Permanente So Calif Reg, San Diego, CA USA

[15] Univ Arizona, Coll Med, Arizona Resp Ctr, Tucson, AZ USA

[16] Pulmatrix, Lexington, MA USA

[17] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pediat Pulmonol & Pediat Allergol,Beatrix Ch, NL-9700 AB Groningen, Netherlands

[18] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pulmonol & TB, NL-9700 AB Groningen, Netherlands

[19] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Epidemiol, NL-9700 AB Groningen, Netherlands

[20] Univ Penn, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA

[21] Overlake Internal Med Associates, Bellevue, WA USA

[22] Brigham & Womens Hosp, Pulm & Crit Care Div, Boston, MA 02115 USA

来源：

PLOS GENETICS | 2012年 / 8卷 / 07期

基金：

美国国家卫生研究院;

关键词：

BETA(2)-ADRENERGIC RECEPTOR; BETA-AGONIST; POLYMORPHISMS; PHARMACOGENETICS; EXPRESSION; ALBUTEROL; PROMOTER; OUTCOMES; THERAPY; RISK;

D O I：

10.1371/journal.pgen.1002824

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 beta(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of beta(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 FEV1 after administration of a beta(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 beta(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of beta(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to beta(2)-agonists through GWAS.

引用

页数：10

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