Jauregi-Miguel Amaia, Santin Izortze, Garcia-Etxebarria Koldo, Olazagoitia-Garmendia Ane, Romero-Garmendia Irati, Sebastian-delaCruz Maialen, Irastorza Iñaki, Castellanos-Rubio Ainara, Bilbao Jose Ramón
Department of Genetics, Physical Anthropology and Animal Physiology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain.
Department of Biochemistry and Molecular Biology, Biocruces-Bizkaia Health Research Institute, University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea), Leioa, Spain.
Front Nutr. 2019 Dec 19;6:187. doi: 10.3389/fnut.2019.00187. eCollection 2019.
Celiac disease (CD) patients present a loss of intestinal barrier function due to structural alterations in the tight junction (TJ) network, the most apical unions between epithelial cells. The association of TJ-related gene variants points to an implication of this network in disease susceptibility. This work aims to characterize the functional implication of TJ-related, disease-associated loci in CD pathogenesis. We performed an association study of 8 TJ-related gene variants in a cohort of 270 CD and 91 non-CD controls. The expression level of transcripts located in the associated SNP region was analyzed by RT-PCR in several human tissues and in duodenal biopsies of celiac patients and non-CD controls. (si)RNA-driven silencing combined with gliadin in the Caco2 intestinal cell line was used to analyze the implication of transcripts from the associated region in the regulation of TJ genes. We replicated the association of rs6962966A variant [ = 0.0029; OR = 1.88 (95%1.24-2.87)], located in an intron of TJ-related MAGI2 coding gene and upstream of RP4-587D13.2 transcript, bioinformatically classified as a long non-coding RNA (lncRNA). The expression of both genes is correlated and constitutively downregulated in CD intestine. Silencing of lncRNA decreases the levels of MAGI2 protein. At the same time, silencing of affects the expression of several TJ-related genes. The associated region is functionally altered in disease, probably affecting CD-related TJ genes.
乳糜泻（CD）患者由于紧密连接（TJ）网络结构改变而出现肠道屏障功能丧失，紧密连接是上皮细胞之间最顶端的连接。TJ相关基因变异的关联表明该网络与疾病易感性有关。这项工作旨在表征TJ相关的疾病相关基因座在CD发病机制中的功能意义。我们在一个由270名CD患者和91名非CD对照组成的队列中对8个TJ相关基因变异进行了关联研究。通过RT-PCR分析了位于相关SNP区域的转录本在几种人体组织以及乳糜泻患者和非CD对照的十二指肠活检中的表达水平。在Caco2肠道细胞系中，将（si）RNA介导的沉默与麦醇溶蛋白相结合，用于分析来自相关区域的转录本在TJ基因调控中的作用。我们重复了rs6962966A变异的关联[ = 0.0029；OR = 1.88（95%1.24 - 2.87）]，该变异位于TJ相关MAGI2编码基因的一个内含子中，在RP4 - 587D13.2转录本上游，生物信息学分类为长链非编码RNA（lncRNA）。这两个基因的表达相关且在CD肠道中组成性下调。lncRNA的沉默降低了MAGI2蛋白的水平。同时， 的沉默影响了几个TJ相关基因的表达。相关区域在疾病中功能改变，可能影响与CD相关的TJ基因。
