The genetics of Crohn's disease.

From epidemiological data, based on concordance data in family studies, via linkage analysis to genome-wide association studies, we and others have accumulated robust evidence implicating more than 30 distinct genomic loci involved in the genetic susceptibility to Crohn's disease (CD). These loci encode genes involved in a number of homeostatic mechanisms: innate pattern recognition receptors (NOD2/CARD15, TLR4, CARD9), the differentiation of Th17-lymphocytes (IL-23R, JAK2, STAT3, CCR6, ICOSLG), autophagy (ATG16L1, IRGM, LRRK2), maintenance of epithelial barrier integrity (IBD5, DLG5, PTGER4, ITLN1, DMBT1, XBP1), and the orchestration of the secondary immune response (HLA-region, TNFSF15/TL1A, IRF5, PTPN2, PTPN22, NKX2-3, IL-12B, IL-18RAP, MST1). While many of these loci also predispose to pediatric CD, an additional number of childhood-onset loci have been identified recently (e.g., TNFRSF6B). Not only has the identification of these loci improved our understanding of the pathophysiology of CD, this knowledge also holds real promise for clinical practice.