Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids
Open accessAbstract
The rs1061170T/C variant encoding the Y402H change in complement factor H (CFH) has been identified by genome-wide association studies as being significantly associated with age-related macular degeneration (AMD). However, the precise mechanism by which this CFH variant impacts the risk of AMD remains largely unknown. Oxidative stress plays an important role in many aging diseases, including cardiovascular disease and AMD. A large amount of oxidized phospholipids (oxPLs) are generated in the eye because of sunlight exposure and high oxygen content. OxPLs bind to the retinal pigment epithelium and macrophages and strongly activate downstream inflammatory cascades. We hypothesize that CFH may impact the risk of AMD by modulating oxidative stress. Here we demonstrate that CFH binds to oxPLs. The CFH 402Y variant of the protective rs1061170 genotype binds oxPLs with a higher affinity and exhibits a stronger inhibitory effect on the binding of oxPLs to retinal pigment epithelium and macrophages. In addition, plasma from non-AMD subjects with the protective genotype has a lower level of systemic oxidative stress measured by oxPLs per apolipoprotein B (oxPLs/apoB). We also show that oxPL stimulation increases expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. OxPLs colocalize with CFH in drusen in the human AMD eye. Subretinal injection of oxPLs induces choroidal neovascularization in mice. In addition, we show that the CFH risk allele confers higher complement activation and cell lysis activity. Together, these findings suggest that CFH influences AMD risk by modulating oxidative stress, inflammation, and abnormal angiogenesis.
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Oxidative stress adducts and components of the complement system accumulate in drusen and sub-RPE deposits of patients with AMD.
“Oxidative stress adducts and components of the complement system have been found to accumulate in drusen and sub-RPE deposits of patients with AMD (Weismann et al., 2011; Shaw et al., 2012), and mice with mutations making them prone to oxidative stress or dysregulation of the complement pathway have been presented as models of AMD (Imamura et al., 2006; Justilien et al., 2007; Hollyfield et al., 2”
From Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis (2015) · cites this paper as Shaw et al., 2012
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- Authors
- Shaw, P. X., Zhang, L., Zhang, M., Du, H., Zhao, L., Lee, C., Grob, S., Lim, S. L., Hughes, G., Lee, J., Bedell, M., Nelson, M. H., Lu, F., Krupa, M., Luo, J., Ouyang, H., Tu, Z., Su, Z., Zhu, J., Wei, X., Feng, Z., Duan, Y., Yang, Z., Ferreyra, H., Bartsch, D.-U., Kozak, I., Zhang, L., Lin, F., Sun, H., Feng, H., & Zhang, K.
- Affiliations
- Sichuan University (CN)
- University of California San Diego (US)
- Institute for Genomic Medicine, and
- North Carolina Macular Consultants, Winston-Salem, NC 27103;
- Molecular Medicine Research Center and Department of Ophthalmology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610064, China;
- Case Western Reserve University (US)
- China Medical University (CN)
- Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (CN)
- Shiley Eye Center, University of California, La Jolla, CA 92093;
- University of California, Los Angeles (US)
- Fengtian Hospital, Shengyang Medical College, Shengyang, Liaoning 110024, China
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-08
- Volume
- 109
- Issue
- 34
- Pages
- 13757-13762
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3427125
- OpenAlex
- W2155641466
- Cited by
- 148
- References
- 49
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 10 · 2023: 9 · 2022: 6 · 2021: 16 · 2020: 8 · 2019: 12 · 2018: 9 · 2017: 8 · 2016: 15 · 2015: 16 · 2014: 14 · 2013: 14 · 2012: 1
- FWCI
- 13.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Eye Institute (R01EY016323, R01EY021374)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- complement factor H, age-related macular degeneration, oxidized phospholipids, rs1061170, oxidative stress, retinal pigment epithelium, macrophages, drusen, choroidal neovascularization, complement activation, inflammation, angiogenesis, genetic susceptibility
- MeSH terms
- Aged, 80 and over, Angiography, Animals, Genotype, Humans, Macular Degeneration, Male, Mice, Inbred C57BL, Oxygen, Phospholipids, Optic Disk Drusen, Complement Factor H, Mice
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