Human complement factor H Y402H polymorphism causes an age-related macular degeneration phenotype and lipoprotein dysregulation in mice

Significance The complement factor H (CFH) Y402H polymorphism (rs1061170) imparts the strongest risk for age-related macular degeneration (AMD), the leading cause of blindness in the elderly. Popular thinking holds that the CFH H402 variant increases complement activation in the eye, predisposing susceptibility to disease. However, clinical trials of complement inhibitors in AMD patients have failed. Here we provide an explanation, showing CFH variant-specific differences in the presentation of AMD-like pathologies. We show that aged mice expressing the human H402, but not Y402 variant, ( i ) develop AMD-like symptoms and ( ii ) display differences in their systemic and ocular lipoprotein levels, but not in their complement activation, after diet. These findings support targeting lipoproteins for the treatment of AMD.