|
|||||
|
|
Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene |
|
| Authors: | Blanca E Himes Gary M Hunninghake Nicholas M Rafaels David P Strachan Saffron AG Willis-Owen Jessica Lasky-Su Amy J Murphy Lydiana Avila Rasika A Mathias Kathleen C Barnes William OC Cookson Frank D Gilliland Christoph Lange George T O'Connor Edwin K Silverman |
| Institution: | 1 Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, 02138, USA 2 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA 3 Children's Hospital Informatics Program, Boston, MA, 02115, USA 4 Partners Center for Personalized Genetic Medicine, Boston, MA, 02115, USA 5 Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA 6 The Johns Hopkins Asthma & Allergy Center, Johns Hopkins University, Baltimore, MD, 21224, USA 7 Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia of the University of Philadelphia School of Medicine, Philadelphia, PA, 19104, USA 8 Community Health Sciences, St George's, University of London, London SW17 ORE, UK 9 School of Medicine, Boston University, Boston, MA, 02118, USA 10 National Heart and Lung Institute, Imperial College, London SW3 6LY, UK 11 Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica 12 Inherited Disease Research Institute, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 21224, USA |
| Abstract: | 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. |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ | |