Association of a Functional Variant in the Wnt Co-Receptor with Early Onset Ileal Crohn's Disease

English version České info

Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD–associated genes including NOD2, ATG16L1, and recently the β-catenin–dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches.

Vyšlo v časopise: Association of a Functional Variant in the Wnt Co-Receptor with Early Onset Ileal Crohn's Disease. PLoS Genet 8(2): e32767. doi:10.1371/journal.pgen.1002523
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002523

Souhrn

Zdroje

1. PodolskyDK 2002 Inflammatory bowel disease. N Engl J Med 347 417 429

2. HalfvarsonJJessTMagnusonAMontgomerySMOrholmM 2006 Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population. Inflamm Bowel Dis 12 925 933

3. SchreiberSRosenstielPAlbrechtMHampeJKrawczakM 2005 Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nat Rev Genet 6 376 388

4. LouisECollardAOgerAFDegrooteEAboul Nasr El YafiFA 2001 Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease. Gut 49 777 782

5. GascheCGrundtnerP 2005 Genotypes and phenotypes in Crohn's disease: do they help in clinical management? Gut 54 162 167

6. SilverbergMSSatsangiJAhmadTArnottIDBernsteinCN 2005 Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 19 Suppl A 5 36

7. KoslowskiMJBeisnerJStangeEFWehkampJ 2009 Innate antimicrobial host defense in small intestinal Crohn's disease. Int J Med Microbiol

8. DuchmannRMayEHeikeMKnollePNeurathM 1999 T cell specifity and cross reactivity towards enterobacteria, Bacteroides, Bifidobacterium, and antigens from resident intestinal flora in humans. Gut 44 812 818

9. SartorRB 2001 Intestinal microflora in human and experimental inflammatory bowel disease. Curr Opin Gastroenterol 17 324 330

10. MacPhersonAKhooUYForgacsIPhilpott-HowardJBjarnasonI 1996 Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 38 365 375

11. SartorRB 1995 Current concepts of the etiology and pathogenesis of ulcerative co and Crohn's disease. Gastroenterol Clin North Am 24 475 507

12. WehkampJKoslowskiMWangGStangeEF 2008 Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn's disease. Mucosal Immunol 1 Suppl 1 S67 S74

13. WehkampJFellermannKHerrlingerKRBevinsCLStangeEF 2005 Mechanisms of disease: defensins in gastrointestinal diseases. Nat Clin Pract Gastroenterol Hepatol 2 406 415

14. WehkampJHarderJWeichenthalMSchwabMSchaffelerE 2004 NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 53 1658 1664

15. WehkampJSalzmanNHPorterENudingSWeichenthalM 2005 Reduced Paneth cell alpha-defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A 102 18129 18134

16. KublerIKoslowskiMJGersemannMFellermannKBeisnerJ 2009 Influence of standard treatment on ileal and colonic antimicrobial defensin expression in active Crohn's disease. Aliment Pharmacol Ther

17. BevinsCPorterEMGanzT 1999 Defensins and innate host defence of the gastrointestinal tract. Gut 45 911 915

18. GeorgeMDWehkampJKaysRJLeuteneggerCMSabirS 2008 In vivo gene expression profiling of human intestinal epithelial cells: analysis by laser microdissection of formalin fixed tissues. BMC Genomics 9 209

19. AyabeTSatchellDPWilsonCLParksWCSelstedME 2000 Secretion of microbicidal alpha-defensins by intestinal Paneth cel response to bacteria. Nat Immunol 1 113 118

20. OguraYInoharaNBenitoAChenFFYamaokaS 2001 Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276 4812 4818

21. OuelletteAJBevinsCL 2001 Paneth cell defensins and innate immunity of the small bowel. Inflamm Bowel Dis 7 43 50

22. SalzmanNHHungKHaribhaiDChuHKarlsson-SjobergJ 2009 Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol

23. OguraYBonenDKInoharaNNicolaeDLChenFF 2001 A frameshift mutation in NOD2 associated with susceptibility to Crohn's diease. Nature 411 603 606

24. KoslowskiMJKublerIChamaillardMSchaeffelerEReinischW 2009 Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. PLoS ONE 4 e4496 doi:10.1371/journal.pone.0004496

25. WehkampJWangGKublerINudingSGregorieffA 2007 The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. J Immunol 179 3109 3118

26. GregorieffACleversH 2005 Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev 19 877 890

27. LiuGBaficoAHarrisVKAaronsonSA 2003 A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. Mol Cell Biol 23 5825 5835

28. SemenovMVTamaiKBrottBKKuhlMSokolS 2001 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol 11 951 961

29. MaoBWuWLiYHoppeDStannekP 2001 LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411 321 325

30. HoffmanJKuhnertFDavisCRKuoCJ 2004 Wnts as essential growth factors for the adult small intestine and colon. Cell Cycle 3 554 557

31. De FerrariGVPapassotiropoulosABiecheleTWavrant De-VriezeFAvilaME 2007 Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc Natl Acad Sci U S A 104 9434 9439

32. PerminowGBeisnerJKoslowskiMLyckanderLGStangeE 2009 Defective Paneth Cell-Mediated Host Defense in Pediatric Ileal Crohn's Disease. Am J Gastroenterol 105 452 459

33. ScherrREssersJHakonarsonHKugathasanS 2009 Genetic determinants of pediatric inflammatory bowel disease: is age of onset genetically determined? Dig Dis 27 236 239

34. ImielinskiMBaldassanoRNGriffithsARussellRKAnneseV 2009 Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41 1335 1340

35. Sagiv-FriedgutKKarbanAWeissBShaoulRShamirR 2010 Early-onset Crohn disease is associated with male sex and a polymorphism in the IL-6 promoter. J Pediatr Gastroenterol Nutr 50 22 26

36. van MeursJBTrikalinosTARalstonSHBalcellsSBrandiML 2008 Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299 1277 1290

37. HainesJLSchnetz-BoutaudNSchmidtSScottWKAgarwalA 2006 Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci 47 329 335

38. SarzaniRSalviFBordicchiaMGuerraFBattistoniI 2009 Carotid artery atherosclerosis in hypertensive patients with a functional LDL receptor-related protein 6 gene variant. Nutr Metab Cardiovasc Dis

39. ManiARadhakrishnanJWangHManiAManiMA 2007 LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315 1278 1282

40. HugotJ-PChamaillardCZoualiHLesageSCezardJ-P 2001 Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411 599 603

41. HampeJFrankeARosenstielPTillATeuberM 2007 A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39 207 211

42. CadwellKLiuJYBrownSLMiyoshiHLohJ 2008 A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456 259 263

43. KaserALeeAHFrankeAGlickmanJNZeissigS 2008 XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134 743 756

44. SimmsLADoeckeJDRobertsRLFowlerEVZhaoZZ 2010 KCNN4 Gene Variant Is Associated With Ileal Crohn's Disease in the Australian and New Zealand Population. Am J Gastroenterol

45. SimmsLADoeckeJDWalshMDHuangNFowlerEV 2008 Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn's disease. Gut 57 903 910

46. BevinsCLStangeEFWehkampJ 2009 Decreased Paneth cell defensin expression in ileal Crohn's disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut 58 882 883

47. WangGStangeEFWehkampJ 2007 Host-microbe interaction: mechanisms of defensin deficiency in Crohn's disease. Expert Rev Anti Infect Ther 5 1049 1057

48. AndreuPColnotSGodardCGadSChafeyP 2005 Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 132 1443 1451

49. TamaiKZengXLiuCZhangXHaradaY 2004 A mechanism for Wnt coreceptor activation. Mol Cell 13 149 156

50. ZengXTamaiKDobleBLiSHuangH 2005 A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438 873 877

51. KorinekVBarkerNMorinPJvanWDdeWR 1997 Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/ −⁠ colon carcinoma. Science 275 1784 1787

52. GersemannMBeckerSKublerIKoslowskiMWangG 2009 Differences in goblet cell differentiation between Crohn's disease and ulcerative colitis. Differentiation 77 84 94