title: A functional variant in IL12B promoter modulates its expression and associates with increased risk of allergic asthma.
abstract: The interleukin-12B (IL12B) gene encodes the p40 chain of IL-12, a pro-inflammatory cytokine that antagonizes Th2 phenotype and, hence, may have a critical role in the pathogenesis of allergic asthma. In this report, we describe the identification of a novel IL12B promoter polymorphism (T-to-A exchange) at position -536. The IL12B -536AA genotype was significantly associated with asthma in the Chinese populations (P=0.011, odds ratio=2.227). The risk-associated A allele was linked to reduced expression of IL12B mRNA levels and IL12B production in asthmatic patients. Luciferase reporter assay provided evidence that risk-associated A allele reduced the promoter activity of IL12B gene compared with those of the promoter containing the protective T allele. We further observed that decreasing binding effects between the risk alleles A of IL12B and CCAAT/enhancer binding protein alpha (C/EBPα) through A allele sequence mediated streptavidin-conjugated agarose pulldown and biotin-labelled A allele mediated electrophoretic mobility shift assay. We also observed additive effects of the risk alleles of IL12B and decreased mRNA levels of C/EBPα in asthmatic patients. Therefore, we postulated that the presence of -536A allele in IL12B promoter could predispose to the development of allergic asthma.
authors.affiliation: Department of Molecular Diagnosis, Shanghai Zhongcheng Translational-medicine Co., Ltd, Shanghai, China. Xuzhonping@gmail.com
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.forename: L
authors.initials: L
authors.lastname: Pei
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: Y
authors.initials: Y
authors.lastname: Gui
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Wu
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000235:genetics*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002681:China; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D012333:RNA, Messenger