Promises, delivery, and challenges of inflammatory bowel disease risk gene discovery

Over the past two decades, investigators have used whole genome linkage and genome-wide association studies, including the "Immunochip" study, to identify a surprising number (over 163) of genetic loci containing susceptibility genes for inflammatory bowel disease (IBD) and its 2 major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC). These loci, although nearly all low-risk, have provided important lessons regarding the nature of IBD etiopathogenesis, including that most loci cause both CD and UC risk; one-third of loci have risk for other common autoimmune diseases; numerous loci contain genes that regulate immunity to microbes; Th17 cells are disproportionately influenced by genes within IBD loci; and the HLA region influences UC far greater than CD. Interleukin-10 receptor subunit (IL10RA and IL10RB) and IL10 cytokine gene mutations cause a rare, severe, infantile-onset, autosomal recessive CD, and this knowledge has allowed curative treatment by bone marrow transplant. Key tasks for broader clinical translation include discovery of risk variants for non-white populations; discovery of the less frequent but higher penetrance and familial risk variants by next-generation sequencing; and determining which of numerous associated variations within loci result in specific gene dysfunction causing IBD risk-as only a small number of genes within IBD loci, including NOD2, IL23R, ATG16L1, IRGM, and PTPN22 have specific functional variations characterized. Studying the effect of IBD susceptiblity gene dysfunctions in tissue cultures and animal models will allow the ultimate translational benefits of developing novel treatments for and potentially preventing IBD in those having specific genetic risk factors.