In their comments on our recently published paper on the genome-wide association study of leprosy (N Engl J Med 2009;361:2609–2618), Watanabe and Chiba reviewed some existing experimental findings that are either supportive or objective for the molecular linkage between Leprosy and Crohn's disease (CD). Although they do recognize that leprosy and CD might share genetic signatures in innate immunity, they question the notion that the increased susceptibility to mycobacterial infections facilitates the development of CD in patients carrying NOD2 mutations. We agree that it is too early to claim that the same causal risk variants increase the susceptibility to both leprosy and CD, because causal variants for leprosy susceptibility within NOD2 are yet to be identified, and NOD2 causal variants for CD have not been shown to increase the susceptibility to mycobacterial infection. Furthermore, it is also worth pointing out that the association between NOD2 polymorphisms and CD has not been established in the Asian population (Gastroenterology 2002;123:86–91; Eur J Human Genet 2003;11:6–16; World J Gastroenterol 2008;14:4923–4927); and the association of NOD2 polymorphisms with leprosy has not been replicated in other populations (N Engl J Med 2010;362:1446–1447). Ethnic heterogeneity of genetic susceptibility to CD and leprosy has further complicated the interpretation of the shared genetic signatures in inner immunity between CD and leprosy. We also want to point out that, beside NOD2 and TNFSF15, C13orf31/CCDC122 at 13q14.11 has also been shown to be a susceptibility locus for CD (Nat Genet 2008;40:955–962), further enhancing the shared genetic signature between the 2 diseases. Functions of C13orf31 and CCDC122 are both unknown. Biological investigation of these genes will likely further illuminate the molecular linkage between the 2 diseases. Last, we want to comment that, although Toll-like receptor signaling, rather than NOD2 signaling, might be important for host defense against M tuberculosis (which is still debatable), NOD2 signaling clearly plays a very important role in host defense against M leprae, and our genome-wide association study of leprosy failed to reveal any association evidence within Toll-like receptor genes (N Engl J Med 2010;362:1446–1447). Card15 Polymorphisms in the Immunopathogenesis of Crohn's Disease and Mycobacterial Infectious DiseasesGastroenterologyVol. 139Issue 6PreviewZhang FR, Huang W, Chen SM, et al. Genomewide association study of leprosy. N Engl J Med 2009;361:2609–2618. Full-Text PDF