aHUS risk factors. There are several risk factors (genetic and environmental) contributing to aHUS pathogenesis. Rare mutations in the complement alternative pathway (AP) proteins factor H, factor I, MCP, C3 or factor B, and in the coagulation protein thrombomodulin reveal a genetic defect in approximately 50% of aHUS patients. Functional characterization of these mutations has established that aHUS results from complement dysregulation that causes defective protection of cellular surfaces. Importantly, complement dysregulation may result from either a defect in the regulatory proteins (loss-of-function) or an abnormally increased activity of the AP complement components (gain-of-function). Anti–factor H autoantibodies with similar consequences that the complement loss-of-function mutations are present in 5% to 10% of aHUS cases. Common polymorphisms in complement AP proteins also contribute to delineate the genetic predisposition to aHUS, either increasing risk or conferring protection. Finally, triggering factors that activate complement modulate aHUS genetic predisposition. In carriers of multiple strong aHUS genetic risk factors, the contribution of the environment is probably minor. On the other hand, strong environmental factors may compensate for low genetic predisposition.