New Genes and Genetic Roles Identified for AMD
Three new variants provide added information.
JOHANNA M. SEDDON, MD, SCM
Nature and nurture contribute to the development of AMD.1,2 Researchers have found common genetic loci in several pathways, including complement, immune, lipid, extracellular matrix, and angiogenesis pathways.2 We have also shown strong associations between AMD and novel rare variants in the CFH, C3, CFI, and C9 genes.3,4
However, the effects of these recently reported genes on AMD progression were unknown, so we determined these effects in new analyses.
OUR RESEARCH
We studied patients from the AREDS cohort whose AMD progressed (N=777) to GA or CNV, as well as nonprogressors (N=1,988), over approximately nine years.
We included in our model the variables of gender, education, smoking history, BMI, and detailed macular phenotypes, including drusen size and the presence of advanced AMD in one eye, as well as 23 genetic variants associated with AMD.5-16
We calculated the area under the curve or receiver operating curve statistic, a measurement of performance of the model, for progression within five years and 10 years.
We also tested the added value of a model with genes vs no genes and models with our previous six genetic variants vs the new model with nine variants, using reclassification methods. It was the first application of this method in ophthalmology.17
WHAT WE FOUND
Our analyses showed that three new genetic variants were significantly correlated with progression to advanced AMD: the rare but strongly related variant in CFH (R1210C), as well as the more recently discovered common variants in the COL8A1 and RAD51B genes.
Johanna M. Seddon, MD, SCM, is director of the Ophthalmic Epidemiology and Genetics Service at the New England Eye Center at Tufts Medical Center and professor of ophthalmology at Tufts University School of Medicine in Boston, MA. She reports no financial interests in products mentioned here. Her e-mail address is jseddon@tuftsmedicalcenter.org.
Our previous six-gene model included common variants in the complement pathway and the ARMS2/HTRA1 gene, and the model with these three new variants (the nine-gene model) performed better, especially for individuals with higher risk scores (Figure 1, page 22).17 Both models with genes performed better than a model without any genes, according to our reclassification analyses (Figure 2, page 22).
Figure 1. The new model with three new genes predicted progression to advanced AMD better than the previous model.
Figure 2. The model also performed better than a model with no genes considered.
CREDIT: PUBLIC LIBRARY OF SCIENCE
To our knowledge, this was the first report of an independent association between progression to advanced AMD and the three new genetic variants — the rare variant in CFH and common variants in the other two genes previously mentioned, controlling for all other known AMD genes and risk factors.
These variants, plus the six included in our previous models, contributed additional predictive information for advanced AMD, beyond macular and behavioral characteristics. Put simply, adding more genes contributed more information.
ADDING TO PREVIOUS FINDINGS
Our first prediction models for advanced AMD in 2006 included only genes.14 We then expanded the models and included demographic and environmental variables, as well as detailed macular phenotypes, and we validated the models with an independent, external validation cohort.18-22
The prediction models included our Markov model of transitions within different stages of AMD and plasma complement levels.21, 22 The addition of plasma complement markers increased the predictability of the model with a C-statistic of 0.91.22
We are currently exploring the mechanisms by which CFH R1210C, COL8A1, and RAD51B genes relate to the development and progression of advanced AMD. The R1210C mutation has been shown to compromise portions of the complement cascade, resulting in defective binding to C3d, C3b, heparin, and endothelial cells.3
The COL8A1 gene encodes one of the two alpha chains of type VIII collagen, a major component of the multiple basement membranes in the eye, including Bruch’s membrane and the choroidal stroma.23 The protein encoded by RAD51B is a member of the RAD51 protein family, and it is essential for DNA repair mechanisms. This gene is also involved in cell cycle delay and apoptosis.24 Individuals with the same macular appearance have different prognoses, depending on their genotypes. Previous studies clearly showed this outcome.18-20
LOOKING AHEAD
Our models are being used for clinical research, for identifying individuals at high risk for increased surveillance, for selecting individuals for inclusion in lower-cost clinical trials of new therapies19, and for assessing different responses to AMD treatments based on the risk score.
We recently reported new rare and highly penetrant genetic loci in the genes C3, CFI, and C9.4 At ARVO in May, we reported that the rare C3 variant is also an indicator of progression.25 As a result, we might further improve the accuracy of our AMD risk prediction models.
Ready or not, the era of personalized medicine is here. RP
REFERENCES
1. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol. 2005;123:321-327.
2. Sobrin L, Seddon JM. Nature and nurture-genes and environment-predicit onset and progrssion of macular degeneration. Prog Retin Eye Res. 2014. 40:1-15.
3. Raychaudhuri S, Iartchouk O, Chin K, et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet. 2011;43:1232-1236.
4. Seddon JM, Yu Y, Miller EC, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet. 2013;45:1366-1370.
5. Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A. 2010;107:7395-7400.
6. Yu Y, Bhangale TR, Fagerness J, et al. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet. 2011;20:3699-3709.
7. Fritsche LG, Chen W, Schu M, et al; AMD Gene Consortium. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45:433-439.
8. Arakawa S, Takahashi A, Ashikawa K, et al. Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nat Genet. 2011;43:1001-1004.
9. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
10. Seddon JM, Sharma S, Adelman RA. Evaluation of the clinical age-related maculopathy staging system. Ophthalmology. 2006;113:260-266.
11. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
12. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet. 2005;77:389-407.
13. Gold B, Merriam JE, Zernant J. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458-462.
14. Maller J, George S, Purcell S, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006;38:1055-1059.
15. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007;39:1200-1201.
16. Seddon JM, George S, Rosner B, Klein ML. CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered. 2006;61:157-165.
17. Seddon JM, Reynolds R, Yu Y, Rosner B. Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration. PLoS One. 2014;9:e87047.
18. Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009;50:2044-2053.
19. Seddon JM, Reynolds R, Yu Y, Daly MJ, Rosner B. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology. 2011;118:2203-2211.
20. Seddon JM, Reynolds R, Yu Y, Rosner B. Validation of a prediction algorithm for progression to advanced macular degeneration subtypes. JAMA Ophthalmol. 2013;131:448-455.
21. Yu Y, Reynolds R, Rosner B, Daly MJ, Seddon JM. Prospective assessment of genetic effects on progression to different stages of age-related macular degeneration using multistate Markov models. Invest Ophthalmol Vis Sci. 2012;21:1548-1556.
22. Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM. Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci. 2009;50:5818-5827.
23. Tamura Y, Konomi H, Sawada H, Takashima S, Nakajima A. Tissue distribution of type VIII collagen in human adult and fetal eyes. Invest Ophthalmol Vis Sci. 1991;32:2636-2644.
24. Suwaki N, Klare K, Tarsounas M. RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin Cell Div Biol. 2011;22:898-905.
25. Seddon J, Reynolds R, Raychaudhuri S, Rosner B. 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:ARVO E-Abstract 4970.
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