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P359. Role of the CYLD protease gene in Crohn's disease, independent from its neighbouring gene CARD15

P359. Role of the CYLD protease gene in Crohn's disease, independent from its neighbouring gene CARD15

I. Cleynen1, M. Artieda2, H.W. Verspaget3, R.K. Weersma4, M. Szczypiorska2, K. Van Steen5, C. Wijmenga4, D.W. Hommes3, P. Rutgeerts1, D. Lottaz6, S. Vermeire1

1KU Leuven, Leuven, Belgium; 2Progenika Biopharma, S.A., Derio, Spain; 3Leiden University Medical Center, Leiden, The Netherlands; 4UMC Groningen, Groningen, The Netherlands; 5Montefiore Institute, Liège, Belgium; 6University of Bern, Bern, Switzerland

Introduction: Proteases and protease inhibitors affect several components that contribute to mucosal barrier integrity, and therefore may be important players in the pathophysiology of Inflammatory Bowel Disease (IBD).

Aims: We aimed to elucidate whether and which proteases/protease inhibitors are involved in IBD pathogenesis.

Materials and Methods: In a first step, a systematic review was performed of all relevant published genetic studies in Crohn's disease (CD) and ulcerative colitis (UC), to prioritize the comprehensive list of known proteases/protease inhibitor genes. From this, an evidence score reflecting the amount of evidence reported on a specific genomic region was calculated, which was then used to rank all known protease/protease inhibitor genes according to their localization within/near these regions. In a following step, the top-ranked genes for CD and UC were followed up in a genetic association study. A total of 185 haplotype tagging SNPs in 23 genes were genotyped in an exploratory cohort of 650 CD (CD1), 721 UC (UC1), and 542 healthy controls (HC1). Replication of SNPs with puncorrected < 0.1 was performed in an independent Dutch cohort of 644 CD (CD2), 529 UC (UC2), and 900 HC (HC2). Cases and controls were compared according to the additive model of inheritance using SNPassoc in R2.9.1. False Discovery Rate (FDR) correction was applied to correct for multiple testing.

Results: All SNPs showing significant associations in the combined cohort (CD1+CD2, UC1+UC2) are shown in Table 1, as well as their possible association in the CD and UC GWAS meta-analyses. Most evidence was found in CYLD, harbouring 2 risk increasing SNPs and 2 protective SNPs (see Table 1). Interestingly, CYLD is located 9kb downstream of CARD15. To test whether the signal seen in CYLD is driven by the well-established CARD15 association, a logistic regression analysis was performed. The final model included both CARD15 and CYLD, pointing to independent signals coming from both genes (pCYLDrs12324931 < 0.001, OR = 2.5 [1.8–3.4]; pCARD15rs2066845 = 0.001, OR = 2.5 [1.4–4.4]; pCARD15rs2066847 < 0.001, OR = 3.8 [2.4–6.1]). In addition, patients not carrying any of the CARD15 variants showed a significant association with rs12324931 (p = 0.002, OR = 5.9 [1.7–20.5]).

Table 1
GeneSNP IDpFDR CD1+CD2Odds Ratio [95% CI]pFDR UC1+UC2Odds Ratio [95% CI]Region associated in CD GWAS meta-analysisRegion associated in UC GWAS meta-analysis
APEHrs21311090.031.2 [1.1–1.7]0.011.2 [1.1–1.4]Yes, 3p21Yes, 3p21
APEHrs111302130.041.2 [1.1–1.3]0.0041.3 [1.1–1.4]Yes, 3p21Yes, 3p21
CYLDrs7205423<0.000011.3 [1.2–1.5]NSYes, 16q12 (CARD15)No
CYLDrs12324931<0.000012.4[1.9–2.9]NSYes, 16q12 (CARD15)No
CYLDrs17314544<0.000010.7 [0.6–0.8]NSYes, 16q12 (CARD15)No
CYLDrs23027590.010.8 [0.7–0.9]NSYes, 16q12 (CARD15)No
DAG1rs6766131NS0.041.2 [1.1–1.3]Yes, 3p21Yes, 3p21
MST1rs9822268NS0.011.2 [1.1–1.4]Yes, 3p21Yes, 3p21
PRSS36rs116492900.040.9 [0.8–1.0]NSNo, but vicinity (18p11)No
PSMB8rs13215NS<0.000011.7 [1.4–2.0]Yes, 6p21 (HLA)Yes, 6p21 (HLA)
PSMB9rs92768310.041.3 [1.1–1.5]0.0021.4 [1.2–1.6]Yes, 6p21 (HLA)Yes, 6p21 (HLA)

Conclusion: We provide strong evidence for association of CYLD on 16q12.1 in CD patients, which is independent from CARD15. CYLD encodes a deubiquitinating enzyme, and is a key negative regulator of NF-κB. CYLD has been shown to be significantly down-regulated in the intestine of IBD patients. Moreover, we identified several other genetic variants in protease/protease inhibitor genes which are implicated in either CD (PRSS36) or UC pathogenesis (DAG1, MST1, PSMB8), or both (APEH, PSMB9).