Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank
Open accessAbstract
To evaluate potential diagnostic and therapeutic biomarkers for age-related macular degeneration (AMD), we identified 8433 UK Biobank participants with rare complement Factor I gene (CFI) variants, 579 with optical coherence tomography-derived macular thickness data. We stratified these variants by predicted gene expression and measured their association with retinal pigment epithelium-Bruch’s membrane (RPE-BM) complex and retinal thicknesses at nine macular subfields, as well as AMD risk, using multivariable regression models adjusted for the common complement Factor H gene (CFH) p.Y402H and age-related maculopathy susceptibility protein 2 gene (ARMS2) p.A69S risk genotypes. CFI variants associated with low Factor I levels predicted a thinner mean RPE-BM (95% confidence interval [CI] −1.66 to −0.37 μm, P = 0.002) and retina (95% CI −5.88 to −0.13 μm, P = 0.04) and a higher AMD risk (odds ratio [OR] = 2.26, 95% CI 1.56 to 3.27, P < 0.001). CFI variants associated with normal Factor I levels did not impact mean RPE-BM/retinal thickness (P = 0.28; P = 0.99) or AMD risk (P = 0.97). CFH p.Y402H was associated with a thinner RPE-BM (95% CI −0.31 to −0.18 μm, P < 0.001 heterozygous; 95% CI −0.62 to −0.42 μm, P < 0.001 homozygous) and retina (95% CI −0.73 to −0.12 μm, P = 0.007 heterozygous; 95% CI −1.08 to −0.21 μm, P = 0.004 homozygous). ARMS2 p.A69S did not influence RPE-BM (P = 0.80 heterozygous; P = 0.12 homozygous) or retinal thickness (P = 0.75 heterozygous; P = 0.07 homozygous). p.Y402H and p.A69S exhibited a significant allele–dose response with AMD risk. Thus, CFI rare variants associated with low Factor I levels are robust predictors of reduced macular thickness and AMD. The observed association between macular thickness and CFH p.Y402H, but not ARMS2 p.A69S, highlights the importance of complement dysregulation in early pathogenesis.
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Some studies have shown that FB has a pro-angiogenic effect mediated through increased VEGF and VEGFR2 expression by endothelial cells in mouse models of laser-induced CNV and retinal hypoxia.
“Some studies have shown that FB has a pro-angiogenic effect mediated through increased VEGF and VEGFR2 expression by endothelial cells in mouse models of laser-induced CNV and retinal hypoxia [81,153,171].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [81]
Our recent study of the UK Biobank found that the common at-risk FH genotype (CFH p.Y402H) and different rare FI variants were associated with reduced RPE-BrM complex thickness in healthy participants, suggesting that complement overactivation may have a negative impact on the function and viability of RPE cells.
“In addition, our recent study of the UK Biobank, the largest repository of retinal imaging data to date, found that the common at-risk FH genotype (CFH p.Y402H) and different rare FI variants were associated with reduced RPE–BrM complex thickness in healthy participants, suggesting that complement overactivation may have a negative impact on the function and viability of RPE cells [81].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [81]
Patients with genetic abnormalities in the complement system tend to only develop overt disease in one organ (such as AMD, C3 glomerulopathy, or atypical haemolytic uraemic syndrome), even in the presence of rare, pathogenic variants or haploinsufficiency of FH and FI.
“patients with genetic abnormalities in the complement system tend to only develop overt disease in one organ (such as AMD, C3 glomerulopathy, or atypical haemolytic uraemic syndrome), even in the presence of rare, pathogenic variants or haploinsufficiency of FH and FI [81,220,221,222,223].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [81]
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The UK Biobank resource with deep phenotyping and genomic data
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- Authors
- Tzoumas, N., Kavanagh, D., Cordell, H. J., Lotery, A. J., Patel, P. J., & Steel, D. H.
- Affiliations
- Newcastle University (GB)
- Royal Victoria Infirmary (GB)
- University of Southampton (GB)
- Moorfields Eye Hospital NHS Foundation Trust (GB)
- Sunderland Eye Infirmary (GB)
- Corresponding author
- Tzoumas, Nikolaos
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-03-14
- Volume
- 31
- Issue
- 16
- Pages
- 2678-2692
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC9402241
- OpenAlex
- W4220805595
- Cited by
- 31
- References
- 51
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 12 · 2023: 5 · 2022: 4
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Institute for Health and Care Research (NF-SI-0515-10020, NF-SI-0507-10094)
- Medical Research Council (MC_PC_17228)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- age-related macular degeneration, complement factor I, macular thickness, retinal thickness, rare variants, biomarkers, complement system, UK Biobank, optical coherence tomography, genetic risk factors
- MeSH terms
- Fibrinogen, Genotype, United Kingdom, Humans, Macular Degeneration, Complement Factor H, Complement Factor I, Biological Specimen Banks, Polymorphism, Single Nucleotide
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