NOD2 and Cowden disease: NOD2 has the largest effect, and a large recent subphenotype-genotype analysis has confirmed that NOD2 is strongly associated in particular with ileal CD.8 Viewed alongside other functionally interrelated genes that have been associated with CD (eg, ATG16L1, IRGM, and XBP1), an impaired capability of the host to regulate microbial constituents consistently emerges as a major common theme.