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BMC Gastroenterology

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Open Access 01-12-2017 | Research article

Genetic variation and expression levels of tight junction genes identifies association between MAGI3 and inflammatory bowel disease

Authors: Elisabeth Norén, Sven Almer, Jan Söderman

Published in: BMC Gastroenterology | Issue 1/2017

Abstract

Background

Inflammatory bowel disease (IBD) is associated with increased intestinal permeability, which involves paracellular passage regulated through tight junctions (TJ). The aim of the study was to investigate single nucleotide polymorphisms (SNP) located in genes encoding interacting TJ proteins and corresponding expressions, in relation to IBD.

Methods

Allelic associations between TJ-related genes (F11R, MAGI1, MAGI2, MAGI3, PARD3, PTEN, and TJP1) and IBD, Crohn’s disease (CD), or ulcerative colitis (UC) were investigated. PTPN22 was included since it’s located in the same genetic region as MAGI3. Gene expression levels were investigated in relation to genotype, inflammatory status, phenotype, and medical treatment.

Results

The two strongest allelic associations were observed between IBD and SNPs in MAGI2 (rs6962966) and MAGI3 (rs1343126). Another MAGI3 SNP marker (rs6689879) contributed to increased ileal MAGI3 expression level in non-IBD controls. Furthermore, association between inflammation and decreased expression levels of MAGI3, PTEN, and TJP1 in colonic IBD as well as UC mucosa, and between inflammation and increased expression of PTPN22 in colonic IBD mucosa, was observed.

Conclusions

Our findings lend support to a genetic basis for modulation of intestinal epithelial barrier in IBD, and we have identified MAGI3 as a new candidate gene for IBD.

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Peloquin JM, Nguyen DD. The microbiota and inflammatory bowel disease: insights from animal models. Anaerobe. 2013;24:102–6.CrossRefPubMed

Loddo I, Romano C. Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis. Front Immunol. 2015;6:551.CrossRefPubMedPubMedCentral

Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48(5):150–8.CrossRef

Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979–86.CrossRefPubMedPubMedCentral

Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.CrossRefPubMedPubMedCentral

John LJ, Fromm M, Schulzke JD. Epithelial barriers in intestinal inflammation. Antioxid Redox Signal. 2011;15(5):1255–70.CrossRefPubMed

Lee SH. Intestinal permeability regulation by tight junction: implication on inflammatory bowel diseases. Intestinal res. 2015;13(1):11–8.CrossRef

Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med. 1986;105(6):883–5.CrossRefPubMed

Vetrano S, Danese S. The role of JAM-A in inflammatory bowel disease: unrevealing the ties that bind. Ann N Y Acad Sci. 2009;1165:308–13.CrossRefPubMed

10.

Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. 2006;55(3):342–7.CrossRefPubMedPubMedCentral

11.

Wapenaar MC, Monsuur AJ, van Bodegraven AA, Weersma RK, Bevova MR, Linskens RK, et al. Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis. Gut. 2008;57(4):463–7.CrossRefPubMed

12.

McGovern DP, Taylor KD, Landers C, Derkowski C, Dutridge D, Dubinsky M, et al. MAGI2 genetic variation and inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(1):75–83.CrossRefPubMedPubMedCentral

13.

KEGG PATHWAY Database. Available at: http://www.genome.jp/kegg/pathway.html (Accessed 19 November 2015).

14.

STRING. Available at: http://string-db.org/. Accessed 16 Aug 2016.

15.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–452.CrossRefPubMed

16.

Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet. 2011;43(11):1066–73.CrossRefPubMedPubMedCentral

17.

Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296(5576):2225–9.CrossRefPubMed

18.

Söderman J, Berglind L, Almer S. Gene Expression-Genotype Analysis Implicates GSDMA, GSDMB, and LRRC3C as Contributors to Inflammatory Bowel Disease Susceptibility. Biomed Res Int. 2015;2015:834805.CrossRefPubMedPubMedCentral

19.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2 (−Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.CrossRefPubMed

20.

Soderman J, Noren E, Christiansson M, Bragde H, Thiebaut R, Hugot JP, et al. Analysis of single nucleotide polymorphisms in the region of CLDN2-MORC4 in relation to inflammatory bowel disease. World J gastroenterol : WJG. 2013;19(30):4935–43.CrossRefPubMedPubMedCentral

21.

Tian C, Gregersen PK, Seldin MF. Accounting for ancestry: population substructure and genome-wide association studies. Hum Mol Genet. 2008;17(R2):R143–150.CrossRefPubMedPubMedCentral

22.

Fasseu M, Treton X, Guichard C, Pedruzzi E, Cazals-Hatem D, Richard C, et al. Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease. PLoS one. 2010;5(10):e13160. doi:10.1371/journal.pone.0013160.

23.

Planell N, Lozano JJ, Mora-Buch R, Masamunt MC, Jimeno M, Ordas I, et al. Transcriptional analysis of the intestinal mucosa of patients with ulcerative colitis in remission reveals lasting epithelial cell alterations. Gut. 2013;62(7):967–76.CrossRefPubMed

24.

Peloquin J, Goel G, Huang H, Haritunians T, Sartor R, Daly M, et al. O-002 Genes in IBD-Associated Risk Loci Demonstrate Genotype-, Tissue-, and Inflammation-Specific Patterns of Expression in Terminal Ileum and Colon Mucosal Tissue. Inflamm Bowel Dis. 2016;22 Suppl 1:S1.CrossRef

25.

Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, et al. Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J Biol Chem. 2000;275(28):21477–85.CrossRefPubMed

26.

Ma Q, Zhang Y, Meng R, Xie KM, Xiong Y, Lin S, et al. MAGI3 Suppresses Glioma Cell Proliferation via Upregulation of PTEN Expression. Biomed environ sci : BES. 2015;28(7):502–9.PubMed

27.

Ma Q, Yang Y, Feng D, Zheng S, Meng R, Fa P, et al. MAGI3 negatively regulates Wnt/beta-catenin signaling and suppresses malignant phenotypes of glioma cells. Oncotarget. 2015;6(34):35851–65.PubMedPubMedCentral

28.

Keerthivasan S, Aghajani K, Dose M, Molinero L, Khan MW, Venkateswaran V, et al. beta-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells. Sci Transl Med. 2014;6(225):225–8.CrossRef

29.

Chen Z, Zhang H, Xia B, Wang P, Jiang T, Song M, et al. Association of PTPN22 gene (rs2488457) polymorphism with ulcerative colitis and high levels of PTPN22 mRNA in ulcerative colitis. Int J Color Dis. 2013;28(10):1351–8.CrossRef

30.

Arimura Y, Yagi J. Comprehensive expression profiles of genes for protein tyrosine phosphatases in immune cells. Sci Signal. 2010;3(137):rs1.CrossRefPubMed

31.

Sharp RC, Abdulrahim M, Naser ES, Naser SA. Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn’s Disease. Front Cell Infect Microbiol. 2015;5:95.CrossRefPubMedPubMedCentral

32.

Langlois MJ, Bergeron S, Bernatchez G, Boudreau F, Saucier C, Perreault N, et al. The PTEN phosphatase controls intestinal epithelial cell polarity and barrier function: role in colorectal cancer progression. PLoS One. 2010;5(12):e15742.CrossRefPubMedPubMedCentral

33.

Zhang L, Shen J, Cheng J, Fan X. MicroRNA-21 regulates intestinal epithelial tight junction permeability. Cell Biochem Funct. 2015;33(4):235–40.CrossRefPubMed

34.

Hu Y, Li Z, Guo L, Wang L, Zhang L, Cai X, et al. MAGI-2 Inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells. Arch Biochem Biophys. 2007;467(1):1–9.CrossRefPubMed

35.

Tokuhira N, Kitagishi Y, Suzuki M, Minami A, Nakanishi A, Ono Y, et al. PI3K/AKT/PTEN pathway as a target for Crohn’s disease therapy (Review). Int J Mol Med. 2015;35(1):10–6.PubMed

36.

Yang Y, Ma Y, Shi C, Chen H, Zhang H, Chen N, et al. Overexpression of miR-21 in patients with ulcerative colitis impairs intestinal epithelial barrier function through targeting the Rho GTPase RhoB. Biochem Biophys Res Commun. 2013;434(4):746–52.CrossRefPubMed

37.

Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008;105(22):7797–802.CrossRefPubMedPubMedCentral

38.

Long SH, He Y, Chen MH, Cao K, Chen YJ, Chen BL, et al. Activation of PI3K/Akt/mTOR signaling pathway triggered by PTEN downregulation in the pathogenesis of Crohn’s disease. J Dig Dis. 2013;14(12):662–9.CrossRefPubMed

39.

Poritz LS, Garver KI, Green C, Fitzpatrick L, Ruggiero F, Koltun WA. Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. J Surg Res. 2007;140(1):12–9.CrossRefPubMed

40.

Toedter G, Li K, Sague S, Ma K, Marano C, Macoritto M, et al. Genes associated with intestinal permeability in ulcerative colitis: changes in expression following infliximab therapy. Inflamm Bowel Dis. 2012;18(8):1399–410.CrossRefPubMed

41.

Arijs I, De Hertogh G, Machiels K, Van Steen K, Lemaire K, Schraenen A, et al. Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment. Am J Gastroenterol. 2011;106(4):748–61.CrossRefPubMed

Title: Genetic variation and expression levels of tight junction genes identifies association between MAGI3 and inflammatory bowel disease
Authors: Elisabeth Norén
Sven Almer
Jan Söderman
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Gastroenterology / Issue 1/2017
Electronic ISSN: 1471-230X
DOI: https://doi.org/10.1186/s12876-017-0620-y

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Genetic variation and expression levels of tight junction genes identifies association between MAGI3 and inflammatory bowel disease

Abstract

Background

Methods

Results

Conclusions

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Abstract

Background

Methods

Results

Conclusions

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