[Show abstract][Hide abstract]ABSTRACT: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.
To identify common genetic variants affecting susceptibility to severe asthma.
A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.
An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.
The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
[Show abstract][Hide abstract]ABSTRACT: 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.
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.
Single nucleotide polymorphisms (SNPs) across the genome were tested for association with increased specific IgE levels (≥ 0.35 kU(A)/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).
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.
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.
Article · Jan 2011 · The Journal of allergy and clinical immunology