The search for susceptibility genes had its first success in 1996, when the first susceptibility locus for CD was identified in the pericentromeric region of chromosome 16, which was called IBD1. In 2001 a caspase recruitment domain-containing protein, CARD15/NOD2, was found to be mutated in 20%–30% of CD patients, establishing a proof of principle for the “genetic concept” of IBD pathophysiology. Multiple mutations in the CARD15/NOD2 gene have been identified (Fig. 3), three of which have been shown to be independently associated with CD (arg702trp, gly908arg, and leu1007fsinsC). 8 These three variants confer a 15%–20% attributable population risk among cases of familial CD. The relevance of CARD15/NOD2 for the etiology of CD was confirmed in a number of subsequent studies. 9, 10 CARD15/NOD2 mutations are associated with ileal disease, earlier age of disease onset, and stricturing disease. 11 In contrast, a few articles support data that CARD15/NOD2 mutations do not play a role in the etiology of CD in Asia12 (see Fig. 3). However, there are several abnormalities in genetic factors of Japanese IBD patients, including the HLA-DR regions. 13, 14 Interestingly, most of these abnormalities are not found in Western countries. In addition, healthy homozygous carriers of the 3020insC frameshift mutation have been described, 15 indicating that CARD15/NOD2 mutations are not the sole determinant of CD and that environmental factors also play an important role. Although epidemiological data concerning CARD15/NOD2 are rather clear and have been con-