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Lookup NU author(s): Tom Hallam, Professor Kevin MarchbankORCiD, Professor Claire Harris, Victoria Shuttleworth, Professor David KavanaghORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Abstract 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 AMD. This study set out to replicate these findings. Methods: FI levels were measured by sandwich ELISA in an independent cohort of 276 AMD patients and 205 elderly controls. SNP genotyping and Sanger sequencing were used to assess genetic variability. Results: The median FI level was significantly lower (28.3μg/mL) in those individuals with AMD and a rare CFI variant compared to those with AMD without a rare CFI variant (38.8μg/mL P = 0.004) or the control population with (41.7μg/mL, P = 0.0085) or without (41.5μg/ml, P < 0.0001) a rare CFI variant. 35% of AMD patients with a rare CFI variant had levels below the 5th 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 for AMD (Early or Late AMD: OR 12.04, 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 humour revealed a large FI concentration gradient between systemic circulation and the eye (~250 -fold). Conclusion: 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.
Author(s): Hallam TM, Marchbank KJ, Harris CL, Osmond C, Shuttleworth VG, Griffiths H, Cree AJ, Kavanagh D, Lotery AJ
Publication type: Article
Publication status: Published
Journal: IOVS
Year: 2020
Volume: 61
Issue: 6
Print publication date: 09/06/2020
Online publication date: 09/06/2020
Acceptance date: 11/04/2020
Date deposited: 14/05/2020
ISSN (electronic): 1552-5783
Publisher: Association for Research in Vision and Ophthalmology
URL: https://doi.org/10.1167/iovs.61.6.18
DOI: 10.1167/iovs.61.6.18
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