June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Impact of protective variants in PELI3 and near CTRB1 on progression to advanced stages of age-related macular degeneration and genetic risk prediction models
Author Affiliations & Notes
  • Johanna M Seddon
    Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States
    Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Boston, Massachusetts, United States
  • Rachel E Silver
    Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Boston, Massachusetts, United States
  • Bernard Rosner
    Channing Division of Network Medicine, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Johanna Seddon, Apellis (C), Novartis (F); Rachel Silver, None; Bernard Rosner, None
  • Footnotes
    Support  JMS: R01-EY011309 from the National Institutes of Health; the Massachusetts Lions Eye Research Fund Inc., New Bedford, MA; and the Age-Related Macular Degeneration Research Fund, Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Tufts University School of Medicine, Boston, MA.; BR: R01-EY022445 from the National Institutes of Health.
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1839. doi:
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    • Get Citation

      Johanna M Seddon, Rachel E Silver, Bernard Rosner; Impact of protective variants in PELI3 and near CTRB1 on progression to advanced stages of age-related macular degeneration and genetic risk prediction models. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1839.

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

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Abstract

Purpose : Our research team recently discovered protective variants in a genetic association study of age-related macular degeneration (AMD) including 4,332 cases and 25,268 controls (Yu Y et al. Hum Molec Genet 2016). In this study, we prospectively evaluated the association between new genetic variants in PELI3 and near CTRB1 and transition to advanced stages of AMD, and incorporated these loci into our previous prediction models (Seddon JM et al. Invest Ophthalmol Vis Sci 2009; Seddon JM et al. Invest Ophthalmol Vis Sci 2015).

Methods : Among 2,906 participants in the Age-Related Eye Disease Study, 828 progressed from no AMD, early AMD, or intermediate AMD to advanced disease, classified as geographic atrophy or neovascular disease. The mean follow-up time was 8.8 years. Novel genetic variants were assessed for independent associations with progression, and survival analysis was used to evaluate multivariate associations between these loci and incident advanced AMD. An age-adjusted area under the curve statistic (AUC) was calculated.

Results : Protective variants in PELI3 (P=0.035) and CTRB1 (P trend<0.0001) were both risk factors for progression to advanced AMD. After adjustment for demographic, behavioral, ocular, and known genetic factors, there was a significant association between PELI3 and progression (hazard ratio [TC vs. CC]: 0.22; 95% confidence interval: 0.06-0.89; P=0.03). For CTRB1, a protective association was suggested per effective allele in the multivariate model (hazard ratio: 0.88; 95% CI: 0.72-1.07), but this result was not statistically significant. Other genetic predictors included 5 common and rare variants in CFH and C3 as well as 5 variants in ARMS2/HTRA1, CFB, C2, COL8A1, and RAD51B. The AUC for progression to advanced AMD for this 12 genetic loci model over 10 years was 0.91.

Conclusions : Models that include risk and protective genetic variants, environmental factors, and macular phenotypes strongly predict disease severity and progression. Our models can facilitate clinical research through the selection of high risk patients for clinical trials, reduction in sample sizes and follow-up time, and lower costs. Such models may play a role in disease management and selection of therapies, and aid in the prevention of visual loss in the evolving era of precision medicine.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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