Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes - 27/02/13
, A. John Henderson, MD a, Nicholas Timpson, PhD b, Beate St. Pourcain, PhD b, John P. Kemp, PhD b, Susan M. Ring, PhD b, Karen Ho, PhD b, Stephen B. Montgomery, PhD c, d, e, Emmanouil T. Dermitzakis, PhD c, David M. Evans, PhD b, Jonathan A.C. Sterne, PhD a
Corresponding author: Raquel Granell, PhD, Avon Longitudinal Study of Parents and Children, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom.Abstract |
Background |
Genome-wide association studies have identified associations of genetic variants at 17q21 near ORMDL3 with childhood asthma.
Objectives |
We sought to determine whether associations in this region are specific to particular asthma phenotypes and specific to ORMDL3.
Methods |
We examined associations between 244 independent single nucleotide polymorphisms (SNPs) plus 13 previously identified asthma-related SNPs in the region between 34 and 36 Mb on chromosome 17 and early wheezing phenotypes, doctor-diagnosed asthma and atopy at 7½ years, and bronchial hyperresponsiveness and lung function at 8½ years in 7045 children from the Avon Longitudinal Study of Parents and Children birth cohort study. With this, cis expression quantitative trait loci signals for the same SNPs were assessed in 875 samples across genes in the same region.
Results |
The strongest evidence for phenotypic association was seen for persistent wheezing (rs8076131 near ORMDL3: relative risk ratio [RRR], 1.60 [95% CI, 1.40-1.84], P = 1.4 × 10−11; rs2305480 near GSDML: RRR, 1.60 [95% CI, 1.39-1.83], P = 1.5 × 10−11; and rs9303277 near IKZF3: RRR, 1.57 [95% CI, 1.37-1.79], P = 4.4 × 10−11). Similar but less precisely estimated effects were seen for intermediate-onset wheeze, but there was little evidence of associations with other wheezing phenotypes. There was some evidence of associations with bronchial hyperresponsiveness. SNPs across the whole region show strong evidence of association with differential levels of expression at GSDML, IKZF3, and MED24, as well as ORMDL3.
Conclusions |
Associations of SNPs in the 17q21 locus are specific to asthma and specific wheezing phenotypes and are not explained by associations with intermediate phenotypes, such as atopy or lung function.
Le texte complet de cet article est disponible en PDF.Key words : Avon Longitudinal Study of Parents and Children, wheezing phenotypes, chromosome 17, ORMDL3, gene expression
Abbreviations used : ALSPAC, BHR, FEF25-75, FVC, GWAS, LD, OR, PARF, Q-Q, RRR, SNP
Plan
| The UK Medical Research Council and the Wellcome Trust (grant reference 092731) and the University of Bristol provide core support for Avon Longitudinal Study of Parents and Children. R.G. was supported by the UK Medical Research Council (grant no. 0401540). J.P.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). |
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| Disclosure of potential conflict of interest: R. Granell and J. A. C. Sterne have been supported by one or more grants from the Medical Research Council UK. A. John Henderson and S. M. Ring have been supported by one or more grants from the Medical Council UK and the Wellcome Trust. B. St Pourcain has received one or more grants from or has one or more grants pending with Autism Speaks and has received one or more payments for lecturing from or is on the speakers’ bureau for Technical University Dresden. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 3
P. 685-694 - mars 2013 Retour au numéro
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