Complement is central to innate immunity with roles in bacterial killing, apoptotic cell clearance and immune complex handling. It is well-recognized that complement is a double-edged sword, with uncontrolled activation contributing to pathology in many diseases. However, the precise way in which complement shifts from protective to destructive roles is not completely understood. Previously we have contributed to understand the association of complement genes with atypical Hemolytic Uremic Syndrome (aHUS), membranoproliferative glomerulonephritis type II (MPGN II) and age-related macular degeneration (AMD). Following this line of research we are currently addressing the study of the functional consequences of different genetic variations of the complement genes asociated to human disease. We believe that these genetic variants alter to different degree the capacity to regulate the complement activation. This complement dysregulation, which may be brought about either by an increased tendency to activate or a diminished capacity to regulate complement, can trigger and/or exacerbate inflammatory damage at specific sites. Using available aHUS, MPGN2 and AMD cohorts we will identified variations in the complement genes CFH, MCP, CFI, CFB, CFHR1/CFHR3, C3, Properdin, DAF, C4BP and CR1 associated with increased risk or protection to these diseases and unravel relevant genotype-phenotype correlations. We will apply routine and newly-developed assays to functionally characterize all identified genetic variations. In addition, we will generate animal models expressing disease-associated variations in complement genes and will explore structural aspects of the formation and regulation of the AP C3-convertase. The knowledge generated will help to understand the molecular basis underlying aHUS, MPGN2, AMD and, likely, other diseases marked by chronic inflammation. It will also facilitate the development of appropriate diagnostics and therapeutics.