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dc.contributor.authorSeddon, Johanna M
dc.contributor.authorRosner, Bernard
dc.contributor.authorDe, Dikha
dc.contributor.authorHuan, Tianxiao
dc.contributor.authorJava, Anuja
dc.contributor.authorAtkinson, John
dc.identifier.citationSeddon 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.en_US
dc.description.abstractPurpose: 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.en_US
dc.relation.ispartofOphthalmology Scienceen_US
dc.rightsCopyright 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.subjectAAMD, advanced age-related macular degenerationen_US
dc.subjectAMD, age-related macular degenerationen_US
dc.subjectAREDS, Age-Related Eye Disease Studyen_US
dc.subjectAdvanced age-related macular degenerationen_US
dc.subjectBMI, body mass indexen_US
dc.subjectC3, complementcomponent 3en_US
dc.subjectC9, complementcomponent 9en_US
dc.subjectCD35, cluster of differentiation 35 (also called complement receptor 1)en_US
dc.subjectCD46, cluster of differentiation 46 (also called membrane cofactor protein)en_US
dc.subjectCFH, complementfactor Hen_US
dc.subjectCFI, complement factor Ien_US
dc.subjectCI, confidence intervalen_US
dc.subjectCOOH, carboxy terminalen_US
dc.subjectCR1, complement receptor 1en_US
dc.subjectComplement factor Ien_US
dc.subjectFI, factor I proteinen_US
dc.subjectGA, geographic atrophyen_US
dc.subjectGRS, genetic risk scoreen_US
dc.subjectGenetic variantsen_US
dc.subjectGeographic atrophyen_US
dc.subjectHR, hazard ratioen_US
dc.subjectNH2, amino terminalen_US
dc.subjectNV, neovascularen_US
dc.subjectNeovascular diseaseen_US
dc.subjectOR, odds ratioen_US
dc.subjectSAS, Statistical Analysis Systemen_US
dc.subjectSLCS, Seddon Longitudinal Cohort Studyen_US
dc.titleRare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degenerationen_US
dc.typeJournal Articleen_US
dc.source.journaltitleOphthalmology science
dc.source.countryUnited States
dc.identifier.journalOphthalmology science
dc.contributor.departmentOphthalmology and Visual Sciencesen_US

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Copyright 2022 by the American Academy of Ophthalmology. This is
an open access article under the CC BY-NC-ND license (
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 (