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P684. Endoplasmic reticulum aminopeptidase 1 is a promising candidate gene for inflammatory bowel disease

D. Laukens1, H. Peeters1, P. Hindryckx1, M. De Vos1, 1Ghent University, Department of Gastroenterology, Gent, Belgium


Genome scan data underscore the importance of genetic susceptibility to inflammatory bowel disease (IBD), and the search for functional gene defects is ongoing. Next to the classical coding mutations, polymorphisms which influence gene expression may have an important impact on gene function. Therefore, we aimed to identify differentially expressed genes in familial IBD that are influenced by the genetic background.


Duplicate genome-wide peripheral blood mononuclear cell (PBMC) expression profiles of 7 families with IBD, containing 15 IBD patients and 32 controls, were generated using Agilent technology. A combination of permutation t-test analysis and heritability score measures was employed to identify differentially expressed genes that are most likely influenced by genetic background. Results were confirmed by quantitative real-time PCR (qRT-PCR) in the same samples and in inflamed biopsies from patients with Crohn's disease (CD, N = 21) and ulcerative colitis (UC, N = 11) and in healthy controls (N = 21). Finally, genotype-expression correlation was investigated in 100 lymphoblastoid cell lines (LCLs) of members of Centre d'Étude du Polymorphisme Humain (CEPH) families.


Based on full gene expression profiles, samples from family members and duplicate samples clustered together. Seven genes were differentially expressed in PBMCs from IBD patients compared to healthy controls and showed positive heritability. Following confirmation by qRT-PCR, genotype-expression analysis of these genes was performed in LCLs of 100 individuals from CEPH families. Of these genes, the expression of endoplasmic reticulum aminopeptidase 1 (ERAP1), a gene that was significantly down-regulated in PBMCs of IBD patients (P = 0.007), had a high heritability score (h2=1.37). In addition, ERAP1 mRNA levels were reduced in inflamed colonic samples of patients with UC and CD compared to healthy colonic tissue (P < 0.001 and P < 0.01 respectively). Finally, various SNPs surrounding the ERAP1 gene, including rs1363907 that was recently associated with IBD, were highly correlated with its expression in LCLs.


Through analyzing gene expression in familial samples, we found that gene expression was highly influenced by genetic background. Reduced expression of ERAP1 was seen in IBD patients, and SNPs surrounding this gene were correlated with its expression. Therefore, ERAP1, a peptidase that is involved in processing proteins for antigen presentation on MHCI, is a promising candidate gene for IBD.