GeneGene Interactions in Inflammatory Bowel Disease: Biological and Clinical Implications

The results of recently completed genome-wide association studies have advanced knowledge of infl ammatory bowel disease (IBD) genetics, including the identifi cation of over 30 genes or loci associated with Crohn ’ s disease (CD). The possibility of interactions between genes, referred to by the term epistasis , needs to be carefully considered as both genetic and functional studies in IBD move forward. We review a paper in this issue of the Journal that reports evidence of epistasis in CD, and we discuss important issues that arise when trying to determine whether there is indeed interaction between genes and what their potential implications for disease pathogenesis and clinical outcome might be. Am J Gastroenterol advance online publication, 12 May 2009; doi: 10.1038/ajg.2009.179 Since the discovery in 2001 of the $ rst in% ammatory bowel disease (IBD)-associated gene, the nucleotide-binding oligomerization domain 2 ( NOD2 ) gene (1,2) , our understanding of the genetics of Crohn ’ s disease (CD) and ulcerative colitis (UC) has rapidly evolved. Most recently, progress in high-throughput genotyping technology and increased knowledge about the human genome through the International HapMap Project and the Human Genome Project have enabled the completion of genome-wide association studies for several complex diseases, including IBD. Such studies have led to the expansion of our knowledge of IBD genetics, leading to the identi$ cation of over 30 CD-associated genes or loci (3) and a growing number of UC-associated genes (4,5) . 9 e genes implicated in such studies, including IL23R , IL12B , IL10 , NOD2 , ATG16L1, and IRGM , have highlighted the important roles of the immune system and of the intestinal tract ’ s interaction with and response to the gut micro% ora in the pathogenesis of IBD. We have also learned that most of the identi$ ed genes individually have only modest e; ects on IBD susceptibility, suggesting that IBD is most likely the result of a combination of several genetic alterations as well as other factors such as environmental in% uences. Given the association of over 30 genes or loci with CD and the $ nding that most of these regions only have modest e; ects on CD susceptibility, it is plausible that there are interactions between genes that further a; ect the risk and clinical course of CD. One possibility is that such interactions, o= en referred to as epistasis, are ubiquitous among common human diseases and even more important than the independent e; ects of any single susceptibility gene (6) . A PubMed search using the words “ epistasis ” and “ IBD ” yields close to 30 publications, underscoring a substantial amount of interest and active investigation in gene – gene interactions in IBD. To further expand our understanding of IBD genetics, potential gene – gene interactions will need to be carefully delineated, especially if they lead to functional alterations or di; erent phenotypic expressions of disease that might otherwise go unrecognized. In addition, the in% uence of environmental factors such as possible environment – gene interactions or modi$ cations also need to be considered. In the study by Torok et al. (7) in this issue of the Journal, the authors follow-up on an earlier report in which they found an association between a polymorphism in the Toll-like receptor 9 ( TLR9 ) gene and CD (8) . In addition, the authors tried to determine whether there are interactions between the TLR9 variant and other CD-associated genes. Toll-like receptors are a family of pattern recognition receptors that play an important role in host defense by recognizing conserved molecular products of microbes and initiating innate immune responses (9) . Some studies have shown possible interactions between NOD2 and TLR proteins, including a recent study showing that functional synergy between Gene – Gene Interactions in Infl ammatory Bowel Disease: Biological and Clinical Implications Jean-Paul Achkar , MD, FACG 1 , 2 and Claudio Fiocchi , MD 1 , 2 1 Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic , Cleveland , Ohio , USA ; 2 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic , Cleveland , Ohio , USA . Correspondence: Jean-Paul Achkar, MD, FACG , Department of Gastroenterology, Cleveland Clinic, 9500 Euclid Avenue, Desk A30, Cleveland, Ohio 44195, USA. E-mail: [email protected] Received 6 February 2009; accepted 17 February 2009