Prager Matthias, Büttner Janine, Grunert Philip, Ellinghaus David, Büning Carsten
*Department of Hepatology and Gastroenterology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany; †Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; and ‡Department of Internal Medicine, Krankenhaus Waldfriede, Berlin, Germany.
Inflamm Bowel Dis. 2016 Oct;22(10):2356-68. doi: 10.1097/MIB.0000000000000910.
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.
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).
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.
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.
吸烟会使克罗恩病（CD）病情恶化。芳烃受体（AhR）是一种转录因子，可介导二噁英类化学物质的毒性。我们推测AhR变异体和吸烟会影响CD。
对AhR基因的外显子 - 内含子边界、编码区和启动子区域进行测序（28例炎症性肠病患者；4例健康对照）。研究了两个已鉴定的变异体（rs7796976和rs2066853）与炎症性肠病患者肠道通透性（IP，口服糖试验）的相关性（根据吸烟状况分层）。通过定量实时聚合酶链反应分析CD患者（n = 53）结肠活检组织中的AhR表达。对这两个变异体进行了病例对照分析，包括基因型 - 表型相关性分析（n = 767例炎症性肠病患者；n = 466例健康对照）。
测序在AhR中鉴定出一个推定的启动子变异体（rs7796976）和一个非同义变异体（rs2066853；Arg554Lys），两者预计都具有功能相关性。rs7796976的主要G等位基因增加了CD患者出现肠道通透性紊乱的风险（比值比1.9，95%置信区间[CI]，1.1 - 3.2），但溃疡性结肠炎患者未出现此情况。我们观察到rs7796976基因型和吸烟对肠道通透性有累加效应（P = 0.005），rs2066853也显示出这种效应（P = 0.004；变异体不连锁）。在CD患者的结肠活检组织中，两个变异体均显示出基因型依赖性的AhR表达。未观察到与CD或溃疡性结肠炎的总体关联；然而，rs7796976基因型和吸烟增加了CD患者出现L4表型的风险。
吸烟和具有功能相关性的AhR变异体会增加CD患者的肠道通透性。由于已知AhR在吸烟和炎症之间起介导作用，这些变异体可能参与了吸烟对CD的有害作用。
