NKX2-3 and Cowden disease: The IBD4 locus harboring abundant immune regulation genes (eg, IL25, IRF9, LTB4R, etc.)demonstrated significant linkage with CD.33 Mean allele sharing of 4 microsatellites in IBD4 is more prominent in families with smoking siblings than in nonsmoking families.34 In addition, smoking showed effect modification on the association between 5p13.1 (rs17234657 and rs9292777), NKX2-3 (rs10883365), IRGM (rs13361189 and rs4958847), CCNY (rs3936503) and PTPN2 (rs2542151), and CD risk.