Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene

被引：253

作者：

Himes, Blanca E. ^{[1
,2
,3
,4
,5
]}

Hunninghake, Gary M. ^{[2
,3
]}

Baurley, James W. ^{[6
]}

Rafaels, Nicholas M. ^{[7
]}

Sleiman, Patrick ^{[8
]}

Strachan, David P. ^{[9
]}

Wilk, Jemma B. ^{[10
]}

Willis-Owen, Saffron A. G. ^{[11
]}

Klanderman, Barbara ^{[2
,3
]}

Lasky-Su, Jessica ^{[2
,3
]}

Lazarus, Ross ^{[2
,3
]}

Murphy, Amy J. ^{[2
,3
]}

Soto-Quiros, Manuel E. ^{[12
]}

Avila, Lydiana ^{[12
]}

Beaty, Terri ^{[7
]}

Mathias, Rasika A. ^{[13
]}

Ruczinski, Ingo ^{[7
]}

Barnes, Kathleen C. ^{[7
]}

Celedon, Juan C. ^{[2
,3
]}

Cookson, William O. C. ^{[11
]}

Gauderman, W. James ^{[6
]}

Gilliland, Frank D. ^{[6
]}

Hakonarson, Hakon ^{[8
]}

Lange, Christoph ^{[2
,3
]}

Moffatt, Miriam F. ^{[11
]}

O'Connor, George T. ^{[10
]}

Raby, Benjamin A. ^{[3
]}

Silverman, Edwin K. ^{[2
,3
]}

Weiss, Scott T. ^{[2
,3
]}

机构：

[1] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02138 USA

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

[3] Harvard Univ, Sch Med, Boston, MA 02115 USA

[4] Childrens Hosp, Informat Program, Boston, MA 02115 USA

[5] Partners Ctr Personalized Genet Med, Boston, MA 02115 USA

[6] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA

[7] Johns Hopkins Univ, Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD 21224 USA

[8] Univ Philadelphia, Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet,Sch Med, Philadelphia, PA 19104 USA

[9] Univ London, London SW17 0RE, England

[10] Boston Univ, Sch Med, Boston, MA 02118 USA

[11] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England

[12] Hosp Nacl Ninos Dr Carlos Saenz Herrera, Div Pediat Pulmonol, San Jose, Costa Rica

[13] NHGRI, Inherited Dis Res Inst, NIH, Baltimore, MD 21224 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2009年 / 84卷 / 05期

基金：

美国国家卫生研究院; 英国惠康基金; 英国医学研究理事会;

关键词：

PHOSPHODIESTERASE 4D GENE; CHILDHOOD ASTHMA; ORMDL3; EXPRESSION; RISK; POLYMORPHISMS; LINKAGE; INHIBITORS; MARKERS; DESIGN; HEART;

D O I：

10.1016/j.ajhg.2009.04.006

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Asthma, a chronic airway disease with known heritability, affects more than 300 million people around the world. A genome-wide association (GWA) study of asthma with 359 cases from the Childhood Asthma Management Program (CAMP) and 846 genetically matched controls from the Illumina ICONdb public resource was performed. The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a regulator of airway smooth-muscle contractility, and PDE4 inhibitors have been developed as medications for asthma. Allelic p values for top SNPs in this region were 4.3 x 10(-07) for rs1588265 and 9.7 x 10(-07) for rs1544791. Replications were investigated in ten independent populations with different ethnicities, study designs, and definitions of asthma. In seven white and Hispanic replication populations, two PDE4D SNPs had significant results with p values less than 0.05, and five had results in the same direction as the original population but had p values greater than 0.05. Combined p values for 18,891 white and Hispanic individuals (4,342 cases) in our replication populations were 4.1 x 10(-04) for rs1588265 and 9.2 x 10(-04) for rs1544791. In three black replication populations, which had different linkage disequilibrium patterns than the other populations, original findings were not replicated. Further study of PDE4D variants might lead to improved understanding of the role of PDE4D in asthma pathophysiology and the efficacy of PDE4 inhibitor medications.

引用

页码：581 / 593

页数：13

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