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Title: Genetic and functional evidence for a role for CYLD in Crohn's disease: Results from a European consortium
Authors: Cleynen, Isabelle
Vazeille, E.
Artieda, M.
Szczypiorska, M.
Bringer, M.-A.
Verspaget, H.
Lakatos, P.
Seibold, F.
Parnell, K.
Weersma, R.
Mahachie, J.
Morgan-Walsh, R.
Staelens, Dominiek
Arijs, Ingrid
Müller, S.
Tordai, A.
Hommes, D.W.
Ahmad, T.
Wijmenga, C.
Pender, S.
Rutgeerts, Paul
Lottaz, D.
Van Steen, Kristel
Vermeire, Séverine
Darfeuille-Michaud, A. #
Issue Date: Feb-2012
Conference: 7th Congress of ECCO edition:7 location:Barcelona, Spain date:16-18 February 2012
Abstract: Background: Data from both humans and experimental animals underscore the critical role of intestinal bacteria in the establishment and maintenance of inflammatory bowel disease (IBD). Host defense to counteract bacterial colonization and maintaining mucosal integrity involves intestinal proteases and protease inhibitors.

Methods: We performed a genetic association study of all top-ranked protease (and inhibitor) genes in a previously published systematic review [1]. 185 haplotype tagging SNPs in 23 genes were genotyped in an exploratory dataset of 650 Crohn's disease (CD) patients, and 542 healthy controls (HC). Validation was performed in 1670 CD and 1254 HC. Statistical analysis was done using SVS v7.5.2 (crude association analysis, additive genetic model), and plink v1.0.7 (meta-analysis of exploration and validation datasets, interaction analysis). A corrected p < 0.05 was considered statistically significant. The T84 epithelial cell line was used for functional assessment of CYLD.

Results: 10 markers were found to be significantly associated with CD in the meta-analysis: 4 in USP40, 1 in APEH, 1 in USP3, and 4 in CYLD. The top signals were in CYLD, a cytoplasmic deubiquitinating enzyme located next to NOD2, on 16q12: rs12324931 (p = 1.64e−18), rs17314544 (p = 1.06e−9), rs7205423 (p = 1.89e−8), and rs1861762 (p = 1.07e−5). A significant interaction between ‘NOD2 overall’ and rs12324931 was found. In patients without any NOD2 risk alleles, a significant CD-risk association with rs12324931 was present (p = 0.001, OR = 4.05 [1.68–9.73]). Upon infection of T84 cells with the adherent-invasive Escherichia coli (AIEC) strain LF82, the prototype strain of AIEC associated with ileal CD, decreased CYLD expression was observed, leading to an increased ability of LF82 AIEC to replicate within T84 cells (through CYLD siRNA transfection). Together with the AIEC LF82-induced CYLD decrease, we observed proteasome-dependent degradation of the NFκB inhibitor, IκB-α, in AIEC LF82 infected T84 cells, and an increased translocation of the NFκB p65 subunit into the nucleus.

Conclusions: Our data provide strong genetic and functional evidence for a role for CYLD in CD pathogenesis. We show that AIEC bacteria are able to take advantage of decreased CYLD to replicate within host epithelial cells, and that CYLD acts as a negative, NFκB-mediated regulator for E. coli colonization.

1. Cleynen I, Juni P, et al. (2011), Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review, PLoS One.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Department of Human Genetics - miscellaneous
Translational Research in GastroIntestinal Disorders
# (joint) last author

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