title: A functional AT/G polymorphism in the 5'-untranslated region of SETDB2 in the IgE locus on human chromosome 13q14.
abstract: The immunoglobulin E (IgE)-associated locus on human chromosome 13q14 influencing asthma-related traits contains the genes PHF11 and SETDB2. SETDB2 is located in the same linkage disequilibrium region as PHF11 and polymorphisms within SETDB2 have been shown to associate with total serum IgE levels. In this report, we sequenced the 15 exons of SETDB2 and identified a single previously ungenotyped mutation (AT/G, rs386770867) in the 5'-untranslated region of the gene. The polymorphism was found to be significantly associated with serum IgE levels in our asthma cohort (P=0.0012). Electrophoretic mobility shift assays revealed that the transcription factor Ying Yang 1 binds to the AT allele, whereas SRY (Sex determining Region Y) binds to the G allele. Allele-specific transcription analysis (allelotyping) was performed in 35 individuals heterozygous for rs386770867 from a panel of 200 British families ascertained through probands with severe stage 3 asthma. The AT allele was found to be significantly overexpressed in these individuals (P=1.26×10(-21)). A dual-luciferase assay with the pGL3 luciferase reporter gene showed that the AT allele significantly affects transcriptional activities. Our results indicate that the IgE-associated AT/G polymorphism (rs386770867) regulates transcription of SETDB2.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Holt
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Vandiedonck
authors.affiliation: Molecular Genomics and Genetics Group, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Willis-Owen
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Knight
authors.affiliation: Molecular Genomics and Genetics Group, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: W O
authors.initials: WO
authors.lastname: Cookson
authors.affiliation: Molecular Genomics and Genetics Group, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: M F
authors.initials: MF
authors.lastname: Moffatt
authors.affiliation: Molecular Genomics and Genetics Group, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000201:enzymology / Q000235:genetics; D002648:Child; D002882:Chromosomes, Human, Pair 13; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011496:Protein Methyltransferases / Q000235:genetics*; D044465:White People
chemical_list: D020121:5' Untranslated Regions; D007073:Immunoglobulin E; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase