Genetics of inflammatory bowel disease: clues to pathogenesis.

INTRODUCTION OR BACKGROUND: It has long been recognized from epidemiological data that inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), have a strong genetic predisposition, interacting with unknown environmental drivers to render susceptible individuals at risk for relapsing intestinal inflammation. Substantial progress has been made in the last 2 years in characterizing the susceptibility genes involved.

SOURCES OF DATA: The recent acceleration in understanding has resulted from the use of new technologies of genome-wide association scanning in large panels of cases and controls.

AREAS OF AGREEMENT: Genome scans have robustly identified 11 susceptibility genes and loci and highlighted a number of new, previously unsuspected pathways as playing an important role in IBD pathogenesis-including the IL23 pathway in IBD overall and specific aspects of innate immunity (particularly NOD2 and the autophagy genes ATG16L1 and IRGM) in CD.

AREAS OF CONTROVERSY: The next challenge is to identify specific causal variants at each of the confirmed susceptibility loci and then characterize their biological impact on gene expression and function of the protein product.

GROWING POINTS: To date, most attention has focused on CD. A recent meta-analysis has increased the number of confirmed susceptibility loci to 32-more than for any other common disease to date. Attention is now turning to the use of the same techniques in UC to identify new, disease-specific genes and understand areas of overlap.

AREAS TIMELY FOR DEVELOPING RESEARCH: This review explores genetic clues to the pathogenesis of IBD derived from the growing list of confirmed IBD susceptibility genes, and briefly elaborates some of the important themes and overlaps that are becoming evident both within IBD and also with other complex diseases.