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Rare genetic variants in complement factor I lead to low FI plasma levels resulting in increased risk of age-related macular degeneration

Rare genetic variants in complement factor I lead to low FI plasma levels resulting in increased risk of age-related macular degeneration
Rare genetic variants in complement factor I lead to low FI plasma levels resulting in increased risk of age-related macular degeneration
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.
Age-related macular degeneration, Aqueous humor, Complement factor I, Complement system, Rare genetic variants
0146-0404
Hallam, Thomas M.
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Marchbank, Kevin J.
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Harris, Claire L.
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Osmond, Clive
2677bf85-494f-4a78-adf8-580e1b8acb81
Shuttleworth, Victoria G.
5febba1e-abf9-4c25-9fc2-457744f3e558
Griffiths, Helen
a097fdaa-d3d6-49a9-9c69-0e6e5a5d518b
Cree, Angela
6724b71b-8828-4abb-971f-0856c2af555e
Kavanagh, David
a2b907e0-308c-47a7-99c1-b19bb7636f01
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Hallam, Thomas M.
deb44b71-5b07-4792-8319-5e6b89fee34c
Marchbank, Kevin J.
2eb7a65f-4471-48f7-abdc-8ec5c1989fc2
Harris, Claire L.
6755ed03-3f71-4a0b-835f-4255924e34e3
Osmond, Clive
2677bf85-494f-4a78-adf8-580e1b8acb81
Shuttleworth, Victoria G.
5febba1e-abf9-4c25-9fc2-457744f3e558
Griffiths, Helen
a097fdaa-d3d6-49a9-9c69-0e6e5a5d518b
Cree, Angela
6724b71b-8828-4abb-971f-0856c2af555e
Kavanagh, David
a2b907e0-308c-47a7-99c1-b19bb7636f01
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514

Hallam, Thomas M., Marchbank, Kevin J., Harris, Claire L., Osmond, Clive, Shuttleworth, Victoria G., Griffiths, Helen, Cree, Angela, Kavanagh, David and Lotery, Andrew (2020) Rare genetic variants in complement factor I lead to low FI plasma levels resulting in increased risk of age-related macular degeneration. Investigative Ophthalmology & Visual Science, 61 (18), [18]. (doi:10.1167/iovs.61.6.18).

Record type: Article

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 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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AMD CFI Manuscript TH Rev 200420 - Accepted Manuscript
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Accepted/In Press date: 11 April 2020
e-pub ahead of print date: 9 June 2020
Keywords: Age-related macular degeneration, Aqueous humor, Complement factor I, Complement system, Rare genetic variants

Identifiers

Local EPrints ID: 441636
URI: http://eprints.soton.ac.uk/id/eprint/441636
ISSN: 0146-0404
PURE UUID: 25167ea9-788f-4c9e-abbc-b58656fdebee
ORCID for Clive Osmond: ORCID iD orcid.org/0000-0002-9054-4655
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 23 Jun 2020 16:30
Last modified: 26 Nov 2021 02:47

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Contributors

Author: Thomas M. Hallam
Author: Kevin J. Marchbank
Author: Claire L. Harris
Author: Clive Osmond ORCID iD
Author: Victoria G. Shuttleworth
Author: Helen Griffiths
Author: Angela Cree
Author: David Kavanagh
Author: Andrew Lotery ORCID iD

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