April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
A New Rare Variant in the C3 Gene Predicts Progression to Advanced Stages of Macular Degeneration and New Predictive Models
Author Affiliations & Notes
  • Johanna Seddon
    Ophthalmology, Tufts University School of Medicine, Boston, MA
  • Robyn Reynolds
    Ophthalmology, Tufts University School of Medicine, Boston, MA
  • Soumya Raychaudhuri
    Genetics, Broad Institute and BWH, Boston, MA
  • Bernard Rosner
    Channing Lab, Brigham and Women's Hospital, Boston, MA
  • Footnotes
    Commercial Relationships Johanna Seddon, Tufts Medical Center (P); Robyn Reynolds, None; Soumya Raychaudhuri, None; Bernard Rosner, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 4970. doi:
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      Johanna Seddon, Robyn Reynolds, Soumya Raychaudhuri, Bernard Rosner; A New Rare Variant in the C3 Gene Predicts Progression to Advanced Stages of Macular Degeneration and New Predictive Models. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4970.

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      © ARVO (1962-2015); The Authors (2016-present)

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We discovered new rare genetic variants in CFH, C3, CFI and C9, which were strongly associated with advanced age-related macular degeneration (AMD) in case-control association studies - Nature Genetics 2011; 43:1232-1236; Nature Genetics 2013; 45:1366-1370. In this study, we determined the independent effects of the new rare C3 variant on conversion from the early and intermediate forms to the advanced stages of AMD, and the impact on our algorithms for predictive modeling.


Participants included 2137 non-progressors and 840 progressors followed over 12 years. New rare genetic loci including a mutation in C3 were assessed for their independent effects on progression to neovascular disease or geographic atrophy using Cox proportional hazards model, controlling for established common genetic loci and demographic, behavioral and macular characteristics. The contribution of genes to risk models was assessed using AUC statistics and reclassification analyses.


The rare C3 variant was independently associated with conversion to advanced stages of AMD, controlling for age, gender, education, body mass index, smoking, baseline AMD severity, macular drusen status and common AMD genetic loci with a hazard ratio (HR) of 1.7, P=.002. A model with the new rare genetic loci in CFH and C3 along with new and established common genetic loci had an AUC of .911 for progression at 10 years. Reclassification analyses suggested an improvement in the model based on adding these new genetic variants for individuals in the higher risk score groups.


The rare C3 genetic variant is independently related to AMD progression. Additional genetic loci enhance accuracy of our predictive models.

Keywords: 412 age-related macular degeneration • 494 degenerations/dystrophies • 539 genetics  

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