Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history

Abstract

Epidemiological data, detailed molecular studies and recent genome-wide association studies strongly suggest that ulcerative colitis (UC) and Crohn’s disease (CD) are related polygenic diseases that share some susceptibility loci, but differ at others. To date, there are more than 50 confirmed inflammatory bowel disease genes/loci, a number that is widely anticipated to at least double in the next 2 years. Germline variation in IL23R, IL12B, JAK2 and STAT3 is associated with inflammatory bowel disease susceptibility, consistent with the newly described role for IL23 signaling and Th17 cells in disease pathogenesis. Several genes involved in different aspects of bacterial handling are defective only in CD, including NOD2 and the autophagy genes ATG16L1 and IRGM. IL10 and ECM1 are associated with UC, while inherited variation at the HLA region is related to an inflammatory colonic phenotype. The application of genome-wide association studies to inflammatory bowel disease has been successful in defining the genetic architecture of CD and UC and in delivering genuinely novel and important insights into disease pathogenesis. This has unearthed a plethora of attractive targets for the development of future therapeutics. Insights into the natural history of these complex diseases will follow and may enable appropriate patient selection for early aggressive therapy with the view to modifying the disease course.

Keywords::

• autophagy
• Crohn’s disease
• genetics
• genome-wide association study
• GLI1
• IL23
• inflammatory bowel disease
• innate immunity
• NOD2
• Th17
• ulcerative colitis

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes

CD: Crohn’s disease; GWAS: Genome-wide association study; HC: Healthy control; IBD: Inflammatory bowel disease; nsSNP: Nonsynonymous single nucleotide polymorphism; SNP: Single nucleotide polymorphism; UC: Ulcerative colitis; WTCCC: Wellcome Trust Case–Control Consortium.

CD: Crohn’s disease; GWAS: Genome-wide association study; HC: Healthy control; IBD: Inflammatory bowel disease; WTCCC: Wellcome Trust Case–Control Consortium.

CD: Crohn’s disease; DSS: Dextran sodium sulfate; GWAS: Genome-wide association study; IBD: Inflammatory bowel disease; nsSNP: Nonsynonymous single nucleotide polymorphism; SNP: Single nucleotide polymorphism; UC: Ulcerative colitis; WT: Wild-type.