Ulcerative colitis is a common form of inflammatory bowel disease (IBD) and is a chronic condition affecting the colon; combined with Crohn’s disease, it affects around 1 in 400 people in the UK (according to the National Association for Colitis and Crohn’s Disease). Over the past two years, several genome wide association studies (GWAS) have expanded the number of genetic factors implicated in IBD pathogenesis, with 32 loci associated with Crohn’s disease and 17 associated with ulcerative colitis. Three research groups have recently published new GWAS studies online in the journal Nature Genetics identifying several new genetic variants.
The study by Asano et al.[Asano et al. (2009) Nat Genet 15 November doi:10.1038/ng.482] reports a two-stage study of Japanese subjects with more than 1,000 ulcerative colitis patients and 3,000 controls. Many SNPs in the MHC region on chromosome 6 showed strong association with IBD. Fifteen SNPs outside this region showing strong association were analysed and three novel susceptibility loci identified: the FCGR2A immunoglobulin receptor gene, the SLC26A3 glycoprotein gene, and a variant on chromosome 13q12.
The second publication by the UK IBD Genetics Consortium and the Wellcome Trust Case Control Consortium 2 [Barrett et al. Nat Genet 15 November doi:10.1038/ng.483] looked at two independent sets of around 2,400 patients with ulcerative colitis and around 5,000 controls. Three new positions on chromosomes 7, 16, and 20 showed significant association with the disease, the authors identified LAMB1, CDH1, and HNF4A as biologically plausible candidate genes in these regions.
The third publication by Imielinski et al. [Imielinski et al. Nat Genet 15 November doi:10.1038/ng.489] reports a GWAS of more than 3,400 European patients with early-onset IBD and almost 12,000 European and North American controls. This study detected associations at 23 of the 32 loci previously implicated in Crohn’s disease and 8 of the 17 previously implicated in ulcerative colitis. It also identified five novel early-onset IBD susceptibility loci on chromosomes 2, 10, 16, 19, and 22. Of the multiple genes in these regions, the authors consider the immunomodulatory cytokine IL27 gene to be the most likely candidate gene involved in disease susceptibility.
Comment: These three well-conducted GWAS papers provide robust evidence for association between several new genetic variants and susceptibility to IBD. Each study identifies biologically plausible candidate genes involved in autoimmunity or the function of the epithelium. For example, the FCGR2A gene is implicated in susceptibility to other autoimmune diseases, and encodes a receptor that is expressed on the surface of several immune cells, whilst the IL27 gene encodes a cytokine which regulates immune cells, lending further support to the idea that this immune pathway plays a key role in causing intestinal inflammation. These susceptibility genes now require extensive follow-up work to understand their role in the processes that cause IBD, which may lead to new approaches in developing treatments.