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

Abstract

One of the strongest susceptibility genes for age-related macular degeneration (AMD) is complement factor H (<i>CFH</i>); 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 (<i>CFH-Y/0</i>) or the AMD-risk associated CFH H402 (<i>CFH-H/H</i>) variant on a <i>Cfh</i>^<i>-/-</i> 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 <i>CFH-H/H</i> mice following the HFC diet. These changes were not observed in aged <i>CFH-Y/0</i> mice or in younger (36- to 40-week-old) <i>CFH</i> mice of both genotypes fed either diet. Biochemical analyses of aged <i>CFH</i> 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 <i>CFH-H/H</i> mice. Specifically, apolipoproteins B48 and A1 are elevated in the RPE/choroid of the aged <i>CFH-H/H</i> mice compared with age-matched control <i>CFH-Y/0</i> 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.