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首页> 外文期刊>Inflammatory bowel diseases >A Promoter Variant Within the Aryl Hydrocarbon Receptor Gene Is Associated with an Epithelial Barrier Defect in Smokers with Crohn's Disease
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A Promoter Variant Within the Aryl Hydrocarbon Receptor Gene Is Associated with an Epithelial Barrier Defect in Smokers with Crohn's Disease

机译：芳基烃受体基因内的启动子变体与克罗恩病的吸烟者中的上皮屏障缺陷有关

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Background:Smoking worsens Crohn's disease (CD). The aryl hydrocarbon receptor (AhR) is a transcription factor that mediates the toxicity of dioxinlike chemicals. We hypothesized that AHR variants and smoking influence CD.Methods:Exon-intron boundaries and coding and promoter regions of AHR gene were sequenced (28 patients with inflammatory bowel disease; 4 healthy controls). Two identified variants (rs7796976 and rs2066853) were studied for an association with intestinal permeability (IP, oral sugar test) in patients with inflammatory bowel disease (stratified according to the smoking status). AHR expression was analyzed by quantitative real-time polymerase chain reaction in colonic biopsies from patients with CD (n = 53). Case-control analysis including a genotype-phenotype correlation was performed for both variants (n = 767 patients with inflammatory bowel disease; n = 466 healthy controls).Results:Sequencing identified a putative promoter variant (rs7796976) and a nonsynonymous variant (rs2066853; Arg554Lys) in AHR, both predicted to be functionally relevant. The major G-allele of rs7796976 increased the risk for disturbed IP (odds ratio 1.9, 95% confidence interval [CI], 1.1-3.2) in CD but not ulcerative colitis. We observed an additive effect of the rs7796976 genotype and smoking on IP (P = 0.005), which was also shown for rs2066853 (P = 0.004; variants not linked). Both variants showed a genotype-dependent AHR expression in colonic biopsies of patients with CD. No overall association with either CD or ulcerative colitis was observed; however, the rs7796976 genotype and smoking increased the risk for the L4 phenotype in CD.Conclusion:Smoking and functionally relevant AHR variants increase IP in CD. Because AhR is known to mediate between smoking and inflammation, these variants might be involved in the deleterious effect of smoking on CD.
机译：背景：吸烟恶化克罗恩病（CD）。芳基烃受体（AHR）是介导二氧化二砷化学物质的毒性的转录因子。我们假设AHR变体和吸烟影响CD.Methods：测序AHR基因的外显子内界和编码和启动子区域（28例炎症肠病; 4例健康对照）。研究了两种鉴定的变体（RS7796976和RS2066853），用于炎症性肠病患者的肠道渗透性（IP，口服糖试验）与炎症性肠病（根据吸烟状态分层）相关联。通过来自CD患者的结肠活组织检查的定量实时聚合酶链反应分析AHR表达（n = 53）。对案例对照分析包括基因型 - 表型相关性对两种变体进行（n = 767例炎症肠道疾病患者; n = 466名健康对照）。结果：测序确定了推定的启动子变体（RS7796976）和非纯文变体（RS2066853; ARG554LYS）在AHR中，两者都预测到功能相关。 RS7796976的主要G-等位基因增加了CD但不溃疡性结肠炎的受干扰IP（差距1.9,95％的置信区间[CI]，1.1-3.2）的风险。我们观察到RS7796976基因型和IP吸烟的添加剂效应（P = 0.005），也显示为RS2066853（P = 0.004;变体没有链接）。两种变体显示出在CD患者的结肠活组织检查中依赖于基因型依赖性AHR表达。没有观察到与CD或溃疡性结肠炎的总体联系;然而，RS7796976基因型和吸烟增加了CD中L4表型的风险。结论：吸烟和功能相关的AHR变体在CD中增加IP。因为已知AHR在吸烟和炎症之间介导，因此这些变体可能参与在CD上吸烟的有害影响。

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