title: A sequence variant on 17q21 is associated with age at onset and severity of asthma.
abstract: 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.
authors.affiliation: Population Genomics, deCODE Genetics Inc., Sturlugata 8, Reykjavik, Iceland.
authors.forename: Eva
authors.initials: E
authors.lastname: Halapi
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Gudrun M
authors.initials: GM
authors.lastname: Jonsdottir
authors.forename: Unnur S
authors.initials: US
authors.lastname: Bjornsdottir
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Hafdis
authors.initials: H
authors.lastname: Helgadottir
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williams
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinzmann
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.forename: Thorarinn
authors.initials: T
authors.lastname: Blondal
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.forename: Adalbjorg
authors.initials: A
authors.lastname: Jonasdottir
authors.forename: Theodora
authors.initials: T
authors.lastname: Thorlacius
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Henry
authors.forename: Janine
authors.initials: J
authors.lastname: Altmueller
authors.forename: Marcus
authors.initials: M
authors.lastname: Krueger
authors.forename: Hyoung Doo
authors.initials: HD
authors.lastname: Shin
authors.forename: Soo-Taek
authors.initials: ST
authors.lastname: Uh
authors.forename: Hyun Sub
authors.initials: HS
authors.lastname: Cheong
authors.forename: Brynja
authors.initials: B
authors.lastname: Jonsdottir
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Ludviksson
authors.forename: Dora
authors.initials: D
authors.lastname: Ludviksdottir
authors.forename: David
authors.initials: D
authors.lastname: Gislason
authors.forename: Choon-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Klaus
authors.initials: K
authors.lastname: Deichmann
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: Matthias
authors.initials: M
authors.lastname: Wjst
authors.forename: Ian P
authors.initials: IP
authors.lastname: Hall
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Thorarinn
authors.initials: T
authors.lastname: Gislason
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: 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
chemical_list: D005819:Genetic Markers; D008565:Membrane Proteins; C464399:ORMDL3 protein, human