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Published on: May 26, 2023
Human complement factor H Y402H polymorphism causes an age-related macular degeneration phenotype and lipoprotein
Michael Landowski1, Una Kelly1, Mikael Klingeborn1
1Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710.
Insights
The complement factor H (CFH) Y402H variant promotes age-related macular degeneration (AMD) like pathology in mice fed a high-fat diet. This suggests targeting lipoproteins may be a viable therapeutic strategy for AMD.
Area of Science:
- Ophthalmology
- Genetics
- Immunology
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss.
- Complement factor H (CFH) is a key genetic susceptibility factor for AMD.
- The precise role of the AMD-risk CFH Y402H variant in AMD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the in vivo effect of the CFH Y402H variant on AMD-like pathology development.
- To determine how diet influences the AMD-like phenotype in mice carrying the CFH Y402H variant.
Main Methods:
- Transgenic mice expressing normal human CFH (Y402) or the AMD-risk variant (H402) were generated on a Cfh-deficient background.
- Mice were aged and fed either a normal diet or a high-fat, cholesterol-enriched (HFC) diet.
- Phenotypic analysis included vision assessment, retinal pigmented epithelium (RPE) stress evaluation, and basal laminar deposit quantification.
- Biochemical analyses focused on plasma and retinal lipoproteins and complement activation.
Main Results:
- Aged mice expressing the CFH H402 variant (CFH-H/H) developed an AMD-like phenotype, including vision loss, RPE stress, and basal laminar deposits, specifically after HFC diet exposure.
- These AMD-like changes were not observed in aged mice with normal CFH (CFH-Y/0) or in younger mice of either genotype.
- Biochemical analysis revealed genotype-dependent alterations in plasma and eyecup lipoproteins, with elevated apolipoproteins B48 and A1 in the RPE/choroid of aged CFH-H/H mice on HFC diet.
- Complement activation levels did not correlate with the observed phenotype.
Conclusions:
- The CFH Y402H polymorphism has a functional consequence in vivo, promoting AMD-like pathology development in aged mice under specific dietary conditions.
- Dietary factors, particularly high-fat/cholesterol intake, can exacerbate the effects of the risk variant.
- These findings highlight the role of lipoproteins in AMD pathogenesis and suggest targeting them as a potential therapeutic strategy.
Abstract:
One of the strongest susceptibility genes for age-related macular degeneration (AMD) is complement factor H (CFH); 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 (CFH-Y/0) or the AMD-risk associated CFH H402 (CFH-H/H) variant on a Cfh 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 CFH-H/H mice following the HFC diet. These changes were not observed in aged CFH-Y/0 mice or in younger (36- to 40-week-old) CFH mice of both genotypes fed either diet. Biochemical analyses of aged CFH 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 CFH-H/H mice. Specifically, apolipoproteins B48 and A1 are elevated in the RPE/choroid of the aged CFH-H/H mice compared with age-matched control CFH-Y/0 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.
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