Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans

Significance Down-regulation of TGFβ signaling is a therapeutic strategy for several disease applications, particularly cancer and fibrosis. However, TGFβ blockade may have adverse effects because TGFβ signaling is necessary for formation and maintenance of normal blood vessels. Because side effects may vary between individuals due to innate differences in genetic makeup, it is important to find which interindividual genetic variants regulate responses to reduced TGFβ signaling and how these operate at the molecular level. Here we identified polymorphic variants of mouse a disintegrin and metalloprotease 17 that differentially regulate TGFβ signaling output and influence the severity ofTgfb1- dependent vascular pathology. This has relevance to risk assessment for clinical manifestations in TGFβ-driven diseases, as well as for prediction of desirable and undesirable responses to anti-TGFβ therapy.