Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration
Seddon, Johanna M ; Rosner, Bernard ; De, Dikha ; Huan, Tianxiao ; Java, Anuja ; Atkinson, John
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UMass Chan Affiliations
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Keywords
AMD, 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 H
CFI, complement factor I
CI, confidence interval
COOH, carboxy terminal
CR1, complement receptor 1
Complement factor I
FI, factor I protein
GA, geographic atrophy
GRS, genetic risk score
Genetic variants
Geographic atrophy
HR, hazard ratio
NH2, amino terminal
NV, neovascular
Neovascular disease
OR, odds ratio
SAS, Statistical Analysis System
SLCS, Seddon Longitudinal Cohort Study
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Abstract
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.