Genetic advances in inflammatory bowel disease

The translation of basic science advances to tangible benefits in clinical practice remains a fundamental goal of biomedical research. Genetic approaches provide a unique opportunity to enhance bench-to-bedside translational efforts, with inflammatory bowel disease (IBD) being a model genetic disorder in several respects. The association of the NOD2 (CARD15) mutations to Crohn's disease (CD) represents, in complex human disorders, one of the clearest cases of a definitive disease association. The NOD2 gene is located in the IBD1 genetic linkage region on chromosome 16 and functions as an intracellular pattern recognition receptor for components of bacterial peptidoglycan. CD-associated variants within NOD2 have a decreased capacity to appropriately signal with peptidoglycan and provide an important example of gene-environment interactions. Genetic variation in other innate immune receptors, notably Toll-like receptor (TLR)4, has been defined and may also play a role in CD pathogenesis. Replicated CD association in the IBD5 region on chromosome 5q has been reported, and candidate functional polymorphisms within the organic cation transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been described. Confirmatory studies demonstrating altered OCTN activity and expression in primary human cells stratified on the IBD5 risk haplotype would provide important confirmatory support for disease contribution. A comprehensive understanding of IBD will involve integrating information from animal models, functional human polymorphisms, and expression studies from human IBD tissues. Genes and pathways implicated as contributing to IBD pathogenesis through multiple lines of evidence should be more intensively examined, including the tumor necrosis factor-α, MDR1, and peroxisome proliferator-activated receptor (PPAR)γ pathways. To attain full advantage of new genetic information, novel methods of classifying patients that go beyond phenotypic classifications presently utilized will be required. Genetic data will need to be integrated with novel biomarker development in IBD, including functional, expression (mRNA or protein), or biochemical indicators of physiologic/disease processes and responses to therapies.