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Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration

Johanna M Seddon1, Bernard Rosner2, Dikha De1

  • 1Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts.

Ophthalmology Science
|March 13, 2023
PubMed

Insights

Rare dysfunctional complement factor I (CFI) variants significantly increase the risk of developing advanced age-related macular degeneration (AMD) with geographic atrophy (GA). This finding highlights CFI's role in AMD progression.

Area of Science:

  • Ophthalmology
  • Genetics
  • Molecular Biology

Background:

  • Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults.
  • Genetic factors play a significant role in AMD pathogenesis.
  • Complement factor I (CFI) is involved in regulating the complement system, a key component of the immune response.

Purpose of the Study:

  • To investigate the association between rare dysfunctional complement factor I (CFI) genetic variants and the progression to advanced AMD, specifically geographic atrophy (GA) and neovascular disease (NV).

Main Methods:

  • A prospective, longitudinal study involving 4953 participants aged 55-80 with non-advanced AMD at baseline.
  • Genotyping and sequencing were used to identify rare CFI variants, categorized as type 1 (associated with low factor I protein levels and function).
  • Generalized estimating equations were employed to assess the association between CFI variants and AMD progression, adjusting for genetic and environmental factors.

Main Results:

  • 1% of participants were identified as type 1 rare CFI carriers.
  • CFI carriers showed a significantly higher progression rate to advanced AMD (44% vs. 20%), GA (30% vs. 10%), and NV (18% vs. 11%) over 12 years compared to non-carriers.
  • CFI carrier status was independently associated with GA progression (OR=1.91) and a higher baseline AMD grade.
  • Higher body mass index (BMI ≥ 25) was associated with increased AMD progression specifically in CFI carriers (OR=5.8).

Conclusions:

  • Carriers of rare dysfunctional type 1 CFI variants face a substantially elevated risk of progressing to advanced AMD with geographic atrophy.
  • These findings underscore the critical role of the complement system, particularly CFI, in AMD development and progression.
  • Elevated BMI may exacerbate AMD progression in individuals with specific CFI genetic profiles.
Abstract

Keywords:
AAMD, advanced age-related macular degenerationAMD, age-related macular degenerationAREDS, Age-Related Eye Disease StudyAdvanced age-related macular degenerationBMI, body mass indexC3, complementcomponent 3C9, complementcomponent 9CD35, 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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