A genome-wide association study to identify genetic determinants of atopy in subjects from the United Kingdom - 10/08/11
, David P. Strachan, MD b, David M. Evans, PhD c, John Henderson, MD d, Tricia McKeever, PhD e, John W. Holloway, BSc, PhD f, Ian P. Hall, DM, FRCP a, Ian Sayers, BSc, PhD a
Reprint requests: Yize I Wan, BMedSci, Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, NG7 2UH, United Kingdom.Abstract |
Background |
A genetic component in the development of atopy has been identified. However, numerous heritability models have been proposed with inconsistent replication of susceptibility loci and genes.
Objective |
We sought to use a genome-wide association study approach to examine genetic susceptibility to atopy, which was defined as increased specific IgE levels, positive skin prick test (SPT) responses, or both, within a large discovery cohort and 3 additional white populations.
Methods |
Single nucleotide polymorphisms (SNPs) across the genome were tested for association with increased specific IgE levels (≥0.35 kUA/L) in the British 1958 Birth Cohort (1083 cases and 2770 control subjects; Illumina 550K Array) to 1 or more allergens, including house dust mite (Der p 1), mixed grass, or cat fur. Independent replication of identified loci (P ≤ .05) was assessed in 3 case-control cohorts from the United Kingdom (n = 3225). Combined analyses of data for top signals across cohorts were conducted for atopic phenotypes: increased specific IgE levels (1378 cases and 3151 control subjects) and positive SPT responses (1058 cases and 2167 control subjects).
Results |
A single SNP on chromosome 13q14 met genome-wide significance (P = 2.15 × 10−9), and a further 6 loci (4.50 × 10−7 ≤ P ≤ 5.00 × 10−5) showed weaker evidence for association with increased specific IgE levels in the British 1958 Birth Cohort. However, no SNPs studied showed consistent association with atopy defined by increased specific IgE levels, positive SPT responses, or both in all study cohorts.
Conclusions |
Seven putative atopy loci were identified using a genome-wide association study approach but showed limited replication across several white populations. This study suggests that large-scale analyses with results from multiple populations will be needed to reliably identify key genetic factors underlying atopy predisposition.
Le texte complet de cet article est disponible en PDF.Key Words : Atopy, specific IgE, skin prick test, genome-wide association study, British 1958 Birth Cohort
Abbreviations used : ALSPAC, FNDC3A, GWAS, SNP, SPT
Plan
| We acknowledge use of phenotype and genotype data from the British 1958 Birth Cohort DNA collection, funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02 (www.b58cgene.sgul.ac.uk/). This analysis uses genotype data deposited by the Wellcome Trust Sanger Institute and by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, which is funded by the Juvenile Diabetes Research Foundation International, the Wellcome Trust, and the National Institute for Health Research Cambridge Biomedical Research Centre; the CIMR is in receipt of a Wellcome Trust Strategic Award (079895). The British 1958 Birth Cohort genotypes deposited by DIL were generated by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD), and the Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. UK Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children Cohort. The Nottingham Gedling cohort collection was funded by Asthma UK and the British Lung Foundation. The Southampton cohort is supported by Asthma, Allergy, and Inflammation Research (AAIR). |
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| Disclosure of potential conflict of interest: J. Henderson receives research support from the Medical Research Council (UK). I. P. Hall receives research support from Asthma UK. The rest of the authors have declared that they have no conflict of interest. |
Vol 127 - N° 1
P. 223 - janvier 2011 Retour au numéro
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