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Three New Genetic Loci (R1210C in CFH, Variants in COL8A1 and RAD51B) Are Independently Related to Progression to Advanced Macular Degeneration

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  • Johanna M Seddon
  • Robyn Reynolds
  • Yi Yu
  • Bernard Rosner

Abstract

Objectives: To assess the independent impact of new genetic variants on conversion to advanced stages of AMD, controlling for established risk factors, and to determine the contribution of genes in predictive models. Methods: In this prospective longitudinal study of 2765 individuals, 777 subjects progressed to neovascular disease (NV) or geographic atrophy (GA) in either eye over 12 years. Recently reported genetic loci were assessed for their independent effects on incident advanced AMD after controlling for 6 established loci in 5 genes, and demographic, behavioral, and macular characteristics. New variants which remained significantly related to progression were then added to a final multivariate model to assess their independent effects. The contribution of genes to risk models was assessed using reclassification tables by determining risk within cross-classified quintiles for alternative models. Results: Three new genetic variants were significantly related to progression: rare variant R1210C in CFH (hazard ratio (HR) 2.5, 95% confidence interval [CI] 1.2–5.3, P = 0.01), and common variants in genes COL8A1 (HR 2.0, 95% CI 1.1–3.5, P = 0.02) and RAD51B (HR 0.8, 95% CI 0.60–0.97, P = 0.03). The area under the curve statistic (AUC) was significantly higher for the 9 gene model (.884) vs the 0 gene model (.873), P = .01. AUC’s for the 9 vs 6 gene models were not significantly different, but reclassification analyses indicated significant added information for more genes, with adjusted odds ratios (OR) for progression within 5 years per one quintile increase in risk score of 2.7, P

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  • Johanna M Seddon & Robyn Reynolds & Yi Yu & Bernard Rosner, 2014. "Three New Genetic Loci (R1210C in CFH, Variants in COL8A1 and RAD51B) Are Independently Related to Progression to Advanced Macular Degeneration," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-11, January.
    • Handle: RePEc:plo:pone00:0087047
    DOI: 10.1371/journal.pone.0087047
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    References listed on IDEAS

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    1. B. Rosner & R. J. Glynn, 2009. "Power and Sample Size Estimation for the Wilcoxon Rank Sum Test with Application to Comparisons of C Statistics from Alternative Prediction Models," Biometrics, The International Biometric Society, vol. 65(1), pages 188-197, March.
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    1. Alvaro Velazquez-Villoria & Sergio Recalde & Jaouad Anter & Jaione Bezunartea & Maria Hernandez-Sanchez & Laura García-García & Elena Alonso & Jose María Ruiz-Moreno & Javier Araiz-Iribarren & Patrici, 2016. "Evaluation of 10 AMD Associated Polymorphisms as a Cause of Choroidal Neovascularization in Highly Myopic Eyes," PLOS ONE, Public Library of Science, vol. 11(9), pages 1-17, September.
    2. Felix Grassmann & Monika Fleckenstein & Emily Y Chew & Tobias Strunz & Steffen Schmitz-Valckenberg & Arno P Göbel & Michael L Klein & Rinki Ratnapriya & Anand Swaroop & Frank G Holz & Bernhard H F Web, 2015. "Clinical and Genetic Factors Associated with Progression of Geographic Atrophy Lesions in Age-Related Macular Degeneration," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-13, May.
    3. Tao Sun & Yi Liu & Richard J. Cook & Wei Chen & Ying Ding, 2019. "Copula-based score test for bivariate time-to-event data, with application to a genetic study of AMD progression," Lifetime Data Analysis: An International Journal Devoted to Statistical Methods and Applications for Time-to-Event Data, Springer, vol. 25(3), pages 546-568, July.

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