Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene.
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.
Himes
Blanca E
BE
Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, 02138, USA. blanca_himes@hms.harvard.edu
Hunninghake
Gary M
GM
Baurley
James W
JW
Rafaels
Nicholas M
NM
Sleiman
Patrick
P
Strachan
David P
DP
Wilk
Jemma B
JB
Willis-Owen
Saffron A G
SA
Klanderman
Barbara
B
Lasky-Su
Jessica
J
Lazarus
Ross
R
Murphy
Amy J
AJ
Soto-Quiros
Manuel E
ME
Avila
Lydiana
L
Beaty
Terri
T
Mathias
Rasika A
RA
Ruczinski
Ingo
I
Barnes
Kathleen C
KC
Celedón
Juan C
JC
Cookson
William O C
WO
Gauderman
W James
WJ
Gilliland
Frank D
FD
Hakonarson
Hakon
H
Lange
Christoph
C
Moffatt
Miriam F
MF
O'Connor
George T
GT
Raby
Benjamin A
BA
Silverman
Edwin K
EK
Weiss
Scott T
ST
D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000208:ethnology / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D055815:Young Adult
D054703:Cyclic Nucleotide Phosphodiesterases, Type 4