Finding Inflammatory Bowel Disease Genes Will Lead to a Cure

Abstract

The opinion that finding inflammatory bowel disease (IBD) genes will lead to a cure is based on the fact that genetic variation provides a vast reservoir of information specific to individual patients that is only beginning to be acknowledged on a large scale. Complementary to this is that, in many respects, IBD represents an ideal genetic disorder(s). First, the significant role of genetics in IBD is firmly established based on the significant familial clustering observed, combined with significantly higher concordance of monozygotic twins compared with dizygotic twins (1). The diagnostic pathogenic certainty associated with the diagnoses of Crohn’s disease (CD) and ulcerative colitis (UC) is high; heterogeneity probably exists in clinically similar cases but is likely relatively limited. Compared with other multigenic disorders, the relevant tissues – the peripheral blood leukocytes and the intestinal tissues – are easy to obtain for expression studies. There are numerous, excellent animal models that exist in IBD (2) for which several lines of evidence provide correlative support in humans. The fact that at least two well-replicated disease associations exist in IBD – nucleotide oligomerization domain 2/caspase activation and recruitment domain 15 (NOD2/CARD15) (3,4) and IBD5 on chromosome 5q (5,6) – holds out the promise that the increased understanding of disease pathophysiology will accrue from genetic approaches. At least three mechanisms can be defined through which genetics can effect cures for IBD. First, if effective, preventive approaches can be developed, feasibly powered studies will require the identification and prospective follow-up of high-risk individuals which will be best achieved through testing of established IBD genes. Second, the identification of genuine IBD risk alleles will often provide very novel insights into the mechanisms of disease pathogenesis that fundamentally change existing paradigms of disease pathogenesis. Finally, genetic approaches refine the understanding of key pathways that lead to human IBD.