Early work on CD-associated NOD2 genetic variants focused on whether these mutationsincreased or decreased the signaling capacity of NOD2.26 A seminal study demonstrated that IL-1β drives colitis in mice with the mouseNOD2 variant equivalent to the human CD variant 3020insC. 27 The authors concluded that this NOD2 variant increased the capacity for NOD2to induce IL-1β directly. Here, NOD2 is linked to Cowden disease.