From as early as 1985, we have been aware that components of cigarette smoke can trigger activation of AP/AL in normal human serum (NHS), possibly modifying C3 in such a way to prevent FH from binding;201 providing an environmentally modified C3 which is similar or more profound than that of the R102G, K155Q, or P314L genetic variants associated with AMD.202, 203, 204. The gene discussed is C3; the disease is age-related macular degeneration.