Genetics of ulcerative colitis

Abstract

Ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic inflammatory bowel diseases (IBDs), with distinct and overlapping susceptibility loci. Recently, hypothesis-free genome-wide association (GWA) studies have revolutionized the field of complex disease genetics. Substantial advances have been achieved in defining the genetic architecture of IBD. To date, over 60 published IBD susceptibility loci have been discovered and replicated, of which approximately a third are associated with both UC and CD, although 21 are specific to UC and 23 to CD. In CD, the breakthrough identification of NOD2 as a susceptibility gene was followed by a rapid phase of gene discovery from GWA studies between 2006 and 2008. Progress in UC was slower; however, by initially testing hits for CD in UC, and later scanning larger UC cohorts, significant new loci for UC have been discovered, with exciting novel insights into disease pathogenesis. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4α, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC. Impaired IL10 signaling has reemerged as a key pathway in intestinal inflammation, and is perhaps the most amenable to therapeutic intervention in UC. Collaborative international efforts with large meta-analyses of GWA studies and replication will yield many new UC genes. Furthermore, a large effort is required to characterize the loci found. Fine-mapping, deep resequencing, and functional studies will be critical to translating these gene discoveries into pathogenic insights, and ultimately into clinical insights and novel therapeutics.

The Changing Face of Inflammatory Bowel Disease: Etiology, Physiopathology, Epidemiology

“…First, encoding the glycoprotein extracellular matrix protein 1 (ECM1) makes a plausible candidate for UC susceptibility: indeed, homozygous nonsense or frameshift mutations of ECM1 have been associated with a rare autosomal manifestation, characterized by skin and gut involvement. Second, mutation of the CDH1 locus, coding for E-cadherin, have been found to be linked with colitis development, in agreement with the notion that E-cadherin, along with HNF4A, effectively maintains barrier integrity (2). Intriguingly, this basic science notion seems to have received support from our real-world clinical experience: in our office, we have recently studied a cluster of IBD patients, who either relapsed or developed de novo a severe UC, after receiving macrolide antibiotics (3).…”

Extracellular matrix protein 1 gene rs3737240 single nucleotide polymorphism is associated with ulcerative colitis in Turkish patients

“…Of these loci, 23 have been identified as unique for UC (20). The identification of the epithelial barrier genes has been the most exciting development in the genetics of UC (21)(22)(23)(24). Many studies show that the disruption of intestinal barrier function leads to IBD (25)(26)(27).…”

miR-20b, miR-98, miR-125b-1*, and let-7e* as new potential diagnostic biomarkers in ulcerative colitis

“…Thus, in order to identify which of the predicted miRNA targets that are actually reported as UC associated susceptibility genes, we used the web application BioVenn [42] (http://www.cmbi. ru.nl/cdd/biovenn/) to compare the list of the miRNA predicted target genes and UC associated susceptibility genes reported in the literature [40,41,[43][44][45] . The UC associated predicted miRNA target genes have been illustrated in a Venn diagram (Figure 4).…”