A genome-wide association study to identify genetic determinants of atopy in subjects from the United Kingdom

Division of Therapeutics and Molecular Medicine, Nottingham Respiratory Biomedical Research Unit, University Hospital of Nottingham, Nottingham, United Kingdom.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 01/2011; 127(1):223-31, 231.e1-3. DOI: 10.1016/j.jaci.2010.10.006
Source: PubMed


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.

7 Reads

  • No preview · Article ·
  • [Show abstract] [Hide abstract]
    ABSTRACT: The licorice-derived compounds glycyrrhizin and 18β-glycyrrhetinic acid have been shown to induce apoptosis in various cancer cells. However, the effect of these licorice compounds on the apoptotic effect of histone deacetylase inhibitors in epithelial ovarian carcinoma cells has not been determined. We assessed the effect of 18β-glycyrrhetinic acid on trichostatin A-induced apoptosis in the human epithelial carcinoma cell lines OVCAR-3 and SK-OV-3. Trichostatin A induced nuclear damage, decreased Bid and Bcl-2 protein levels, increased in Bax levels, induced cytochrome c release, activated caspase-8, -9 and -3, and increased tumor suppressor p53 levels. 18β-Glycyrrhetinic acid potentiated the trichostatin A-induced apoptosis-related protein activation and cell death. Unlike 18β-glycyrrhetinic acid, up to 25 μM of the pro-compound glycyrrhizin did not induce cell death and did not affect trichostatin A-induced apoptosis. The results suggest that 18β-glycyrrhetinic acid may potentiate the apoptotic effects of trichostatin A against ovarian carcinoma cell lines by increasing the activation of the caspase-8-dependent pathway as well as the activation of the mitochondria-mediated cell death pathway, leading to activation of caspases. 18β-Glycyrrhetinic acid may enhance the therapeutic effect of trichostatin A against epithelial ovarian adenocarcinoma.
    No preview · Article · Dec 2010 · European journal of pharmacology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The last years have witnessed novel findings with exciting developments in the field of allergy-related diseases including asthma, bronchial hyperresponsiveness, eczema, and atopy that have enormously increased over the past few years. This issue of the Reviews is timely dedicated to comprehensive articles discussing the current trends in the study of these conditions. In particular, the impact of new data in genomics, environmental factors through epigenetics and proteomics will be reviewed and critically discussed.
    No preview · Article · Apr 2011 · Clinical Reviews in Allergy & Immunology
Show more