Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration
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Publisher version
UMass Chan Affiliations
Ophthalmology and Visual SciencesDocument Type
Journal ArticlePublication Date
2022-12-30Keywords
AAMD, advanced age-related macular degenerationAMD, age-related macular degeneration
AREDS, Age-Related Eye Disease Study
Advanced age-related macular degeneration
BMI, body mass index
C3, complementcomponent 3
C9, complementcomponent 9
CD35, cluster of differentiation 35 (also called complement receptor 1)
CD46, cluster of differentiation 46 (also called membrane cofactor protein)
CFH, complementfactor HCFI, complement factor ICI, confidence intervalCOOH, carboxy terminalCR1, complement receptor 1Complement factor IFI, factor I proteinGA, geographic atrophyGRS, genetic risk scoreGenetic variantsGeographic atrophyHR, hazard ratioNH2, amino terminalNV, neovascularNeovascular diseaseOR, odds ratioSAS, Statistical Analysis SystemSLCS, Seddon Longitudinal Cohort Study
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Purpose: To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV). Design: Prospective, longitudinal study. Participants: Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. Methods: Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. Main outcome measures: Progression to AAMD, GA, or NV. Results: In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P < 0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.03, 3.52) but not NV (OR = 0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs. < 25; OR = 5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011. Conclusions: Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA. Financial disclosures: Proprietary or commercial disclosure may be found after the references.Source
Seddon JM, Rosner B, De D, Huan T, Java A, Atkinson J. Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration. Ophthalmol Sci. 2022 Dec 30;3(2):100265. doi: 10.1016/j.xops.2022.100265. PMID: 36909148; PMCID: PMC9993025.DOI
10.1016/j.xops.2022.100265Permanent Link to this Item
http://hdl.handle.net/20.500.14038/53317PubMed ID
36909148Rights
Copyright 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).; Attribution-NonCommercial-NoDerivatives 4.0 InternationalDistribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/Scopus Count
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Except where otherwise noted, this item's license is described as Copyright 2022 by the American Academy of Ophthalmology. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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