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

One of the strongest susceptibility genes for age-related macular degeneration (AMD) is complement factor H (); however, its impact on AMD pathobiology remains unresolved. Here, the effect of the principal AMD-risk-associated CFH variant (Y402H) on the development and progression of age-dependent AMD-like pathologies was determined in vivo. Transgenic mice expressing equal amounts of the full-length normal human CFH Y402 () or the AMD-risk associated CFH H402 () variant on a background were aged to 90 weeks and switched from normal diet (ND) to a high fat, cholesterol-enriched (HFC) diet for 8 weeks. The resulting phenotype was compared with age-matched controls maintained on ND. Remarkably, an AMD-like phenotype consisting of vision loss, increased retinal pigmented epithelium (RPE) stress, and increased basal laminar deposits was detected only in aged mice following the HFC diet. These changes were not observed in aged mice or in younger (36- to 40-week-old) mice of both genotypes fed either diet. Biochemical analyses of aged mice after HFC diet revealed genotype-dependent changes in plasma and eyecup lipoproteins, but not complement activation, which correlated with the AMD-like phenotype in old mice. Specifically, apolipoproteins B48 and A1 are elevated in the RPE/choroid of the aged mice compared with age-matched control fed a HFC diet. Hence, we demonstrate a functional consequence of the Y402H polymorphism in vivo, which promotes AMD-like pathology development and affects lipoprotein levels in aged mice. These findings support targeting lipoproteins as a viable therapeutic strategy for treating AMD.