Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration.
OBJECTIVE
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<0.001 for the 9 vs 6 loci model, and OR 3.5, P<0.001 for the 9 vs. 0 gene model. Similar results were seen for NV and GA.


CONCLUSIONS
Rare variant CFH R1210C and common variants in COL8A1 and RAD51B plus six genes in previous models contribute additional predictive information for advanced AMD beyond macular and behavioral phenotypes.
Ophthalmic Epidemiology and Genetics Service, Tufts University School of Medicine and Tufts Medical Center, New England Eye Center, Boston, Massachusetts, United States of America ; Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Johanna M
JM
Seddon
Ophthalmic Epidemiology and Genetics Service, Tufts University School of Medicine and Tufts Medical Center, New England Eye Center, Boston, Massachusetts, United States of America.
Robyn
R
Reynolds
Ophthalmic Epidemiology and Genetics Service, Tufts University School of Medicine and Tufts Medical Center, New England Eye Center, Boston, Massachusetts, United States of America.
Yi
Y
Yu
Channing Laboratory, Brigham and Women's Hospital and Harvard School of Public Health, Harvard University, Boston, Massachusetts, United States of America.
Bernard
B
Rosner
D000368:Aged; D024102:Collagen Type VIII / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D016019:Survival Analysis
D024102:Collagen Type VIII; D004268:DNA-Binding Proteins; C413002:RAD51B protein, human; D017242:Complement Factor H