TY - JOUR
T1 - Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene
AU - Himes, Blanca E.
AU - Hunninghake, Gary M.
AU - Baurley, James W.
AU - Rafaels, Nicholas M.
AU - Sleiman, Patrick
AU - Strachan, David P.
AU - Wilk, Jemma B.
AU - Willis-Owen, Saffron A.G.
AU - Klanderman, Barbara
AU - Lasky-Su, Jessica
AU - Lazarus, Ross
AU - Murphy, Amy J.
AU - Soto-Quiros, Manuel E.
AU - Avila, Lydiana
AU - Beaty, Terri
AU - Mathias, Rasika A.
AU - Ruczinski, Ingo
AU - Barnes, Kathleen C.
AU - Celedón, Juan C.
AU - Cookson, William O.C.
AU - Gauderman, W. James
AU - Gilliland, Frank D.
AU - Hakonarson, Hakon
AU - Lange, Christoph
AU - Moffatt, Miriam F.
AU - O'Connor, George T.
AU - Raby, Benjamin A.
AU - Silverman, Edwin K.
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 protections. The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, and T32 HL07427 from the NHLBI, National Institutes of Health (NIH). Additional support was provided by the following NIH grants: R37 HL066289, 5R01HL087680 (NHLBI); 5P01ES011627, and 5P30ES007048 (National Institute of Environmental Health Sciences); and 2T15LM007092-16 (National Library of Medicine). We acknowledge use of genotype data from the B58C DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. We are grateful to John Todd, Diabetes & Inflammation Laboratory, University of Cambridge, and Panos Deloukas, Wellcome Trust Sanger Institute, for depositing genotype data on the B58C. K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. R.A.M. was supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. We thank Georgia Dunston and Mezbah Faruque from Howard University, Washington, DC, for their vital contribution in the recruitment of the GRAAD1 cohort.
PY - 2009/5/15
Y1 - 2009/5/15
N2 - 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 × 10-07 for rs1588265 and 9.7 × 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 × 10-04 for rs1588265 and 9.2 × 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.
AB - 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 × 10-07 for rs1588265 and 9.7 × 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 × 10-04 for rs1588265 and 9.2 × 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.
UR - http://www.scopus.com/inward/record.url?scp=65549123032&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65549123032&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2009.04.006
DO - 10.1016/j.ajhg.2009.04.006
M3 - Article
C2 - 19426955
AN - SCOPUS:65549123032
SN - 0002-9297
VL - 84
SP - 581
EP - 593
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -