Variants of DENND1B associated with asthma in children.
BACKGROUND
Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.


METHODS
We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls.


RESULTS
In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected].


CONCLUSIONS
We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.
Sleiman
Patrick M A
PM
Center for Applied Genomics, Philadelphia, PA 19104-4318, USA.
Flory
James
J
Imielinski
Marcin
M
Bradfield
Jonathan P
JP
Annaiah
Kiran
K
Willis-Owen
Saffron A G
SA
Wang
Kai
K
Rafaels
Nicholas M
NM
Michel
Sven
S
Bonnelykke
Klaus
K
Zhang
Haitao
H
Kim
Cecilia E
CE
Frackelton
Edward C
EC
Glessner
Joseph T
JT
Hou
Cuiping
C
Otieno
F George
FG
Santa
Erin
E
Thomas
Kelly
K
Smith
Ryan M
RM
Glaberson
Wendy R
WR
Garris
Maria
M
Chiavacci
Rosetta M
RM
Beaty
Terri H
TH
Ruczinski
Ingo
I
Orange
Jordan S
JS
Orange
Jordan M
JM
Allen
Julian
J
Spergel
Jonathan M
JM
Grundmeier
Robert
R
Mathias
Rasika A
RA
Christie
Jason D
JD
von Mutius
Erika
E
Cookson
William O C
WO
Kabesch
Michael
M
Moffatt
Miriam F
MF
Grunstein
Michael M
MM
Barnes
Kathleen C
KC
Devoto
Marcella
M
Magnusson
Mark
M
Li
Hongzhe
H
Grant
Struan F A
SF
Bisgaard
Hans
H
Hakonarson
Hakon
H
D001249:Asthma / Q000235:genetics*; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002878:Chromosomes, Human, Pair 1; D002886:Chromosomes, Human, Pair 17; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D009656:North America; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D044465:White People / Q000235:genetics*
C546321:DENND1B protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D018124:Receptors, Tumor Necrosis Factor