Rare genetic variants in complement factor I lead to low FI plasma levels resulting in increased risk of age-related macular degeneration
Open accessAbstract
Purpose: Rare genetic variants in complement factor I (CFI) that cause low systemic levels of the protein (FI) have been reported as a strong risk factor for advanced age-related macular degeneration (AMD). This study set out to replicate these findings. Methods: FI levels were measured by sandwich ELISA in an independent cohort of 276 patients with AMD and 205 elderly controls. Single-nucleotide polymorphism genotyping and Sanger sequencing were used to assess genetic variability. Results: The median FI level was significantly lower in those individuals with AMD and a rare CFI variant (28.3 µg/mL) compared to those with AMD without a rare CFI variant (38.8 µg/mL, P = 0.004) or the control population with (41.7 µg/mL, P = 0.0085) or without (41.5 µg/mL, P < 0.0001) a rare CFI variant. Thirty-six percent of patients with AMD with a rare CFI variant had levels below the fifth percentile, compared to 6% in controls with CFI variants. Multiple regression analyses revealed a decreased FI level associated with a rare CFI variant was a risk factor for AMD (early or late AMD: odds ratio [OR] 12.05, P = 0.03; early AMD: OR 30.3, P = 0.02; late AMD: OR 10.64, P < 0.01). Additionally, measurement of FI in aqueous humor revealed a large FI concentration gradient between systemic circulation and the eye (∼286-fold). Conclusions: Rare genetic variants in CFI causing low systemic FI levels are strongly associated with AMD. The impermeability of the Bruch's membrane to FI will have implications for therapeutic replacement of FI in individuals with CFI variants and low FI levels at risk of AMD.
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FI is found at significantly lower levels in the aqueous fluid of the eye compared to FI levels in simultaneously sampled serum.
“FI is found at significantly lower levels in the aqueous fluid of the eye compared to FI levels found in simultaneously sampled serum [211].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [211]
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- Authors
- Hallam, T. M., Marchbank, K. J., Harris, C. L., Osmond, C., Shuttleworth, V. G., Griffiths, H., Cree, A. J., Kavanagh, D., & Lotery, A. J.
- Affiliations
- Royal Victoria Infirmary (GB)
- MRC Lifecourse Epidemiology Unit (GB)
- University of Southampton (GB)
- Corresponding author
- Lotery, Andrew J.
- ORCID
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2020-06-09
- Volume
- 61
- Issue
- 6
- Pages
- 18
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC7415286
- OpenAlex
- W3034151544
- Cited by
- 57
- References
- 44
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 10 · 2023: 10 · 2022: 16 · 2021: 7 · 2020: 1
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0515-10020)
- Medical Research Council (1786288)
- 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 I, age-related macular degeneration, rare variants, aqueous humor, complement system, genetic risk factors
- MeSH terms
- Aged, Aged, 80 and over, Eye Proteins, Female, Genetic Testing, Humans, Macular Degeneration, Male, Middle Aged, Proteins, Retrospective Studies, Risk Factors, Genetic Variation, Biomarkers, Proportional Hazards Models, Case-Control Studies, Complement Factor H, Complement Factor I, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Vascular Endothelial Growth Factor A, Receptors, TNF-Related Apoptosis-Inducing Ligand, Genotyping Techniques
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