Abstract
BackgroundGenome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes.Methodology/Principal FindingsA total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10−5; 0.76 [0.67–0.87]) and of rs7720838 (p = 6.91×10−4; 0.81 [0.71–0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10−7 for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.Conclusions/SignificanceWe confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.
Highlights
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) characterized by a complex molecular pathogenesis resulting in an exaggerated immune response and mucosal destruction [1,2,3]
Since the identification of NOD2 as the first susceptibility gene for CD in 2001 [5,6], various studies including genome-wide association studies (GWAS) based on high-density SNP arrays have identified CD-associated genetic variants of proteins involved in immune response, autophagy or bacterial recognition, such as IL23R [7,8], ATG16L1 [9,10,11], and IRGM [12]
We could not replicate a contribution of the 5p13.1 region to UC susceptibility which was demonstrated by recent meta-analyses of GWAS [29,36] and may be related to the limited sample size of our cohort and the weaker effect of the 5p13.1 region on UC susceptibility compared to CD susceptibility
Summary
Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) characterized by a complex molecular pathogenesis resulting in an exaggerated immune response and mucosal destruction [1,2,3]. Since the identification of NOD2 as the first susceptibility gene for CD in 2001 [5,6], various studies including genome-wide association studies (GWAS) based on high-density SNP (single nucleotide polymorphism) arrays have identified CD-associated genetic variants of proteins involved in immune response, autophagy or bacterial recognition, such as IL23R [7,8], ATG16L1 [9,10,11], and IRGM [12]. Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn’s disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes
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