A sequence variant on 17q21 is associated with age at onset and severity of asthma.
A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.
Halapi
Eva
E
Population Genomics, deCODE Genetics Inc., Sturlugata 8, Reykjavik, Iceland.
Gudbjartsson
Daniel F
DF
Jonsdottir
Gudrun M
GM
Bjornsdottir
Unnur S
US
Thorleifsson
Gudmar
G
Helgadottir
Hafdis
H
Williams
Carolyn
C
Koppelman
Gerard H
GH
Heinzmann
Andrea
A
Boezen
H Marike
HM
Jonasdottir
Aslaug
A
Blondal
Thorarinn
T
Gudjonsson
Sigurjon A
SA
Jonasdottir
Adalbjorg
A
Thorlacius
Theodora
T
Henry
Amanda P
AP
Altmueller
Janine
J
Krueger
Marcus
M
Shin
Hyoung Doo
HD
Uh
Soo-Taek
ST
Cheong
Hyun Sub
HS
Jonsdottir
Brynja
B
Ludviksson
Bjorn R
BR
Ludviksdottir
Dora
D
Gislason
David
D
Park
Choon-Sik
CS
Deichmann
Klaus
K
Thompson
Philip J
PJ
Wjst
Matthias
M
Hall
Ian P
IP
Postma
Dirkje S
DS
Gislason
Thorarinn
T
Kong
Augustine
A
Jonsdottir
Ingileif
I
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
D000293:Adolescent; D017668:Age of Onset; D001249:Asthma / Q000453:epidemiology* / Q000235:genetics*; D001315:Australia / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005786:Gene Expression Regulation; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D007723:Korea / Q000453:epidemiology; D008565:Membrane Proteins; D020641:Polymorphism, Single Nucleotide
D005819:Genetic Markers; D008565:Membrane Proteins; C464399:ORMDL3 protein, human