Risk in AMD: Insight from Studies on Environmental Risk Factors, Genotype, and VEGF

Mary Elizabeth Hartnett, MD

Associate Professor of Ophthalmology, University of North Carolina School of Medicine

Studies have shown that both environmental risk factors, such as smoking and body mass index^1,2, and genotype^3-8 are important in determining individuals at risk for vision loss due to AMD⁹. However, how to interpret these data is difficult, particularly when advising an individual patient. This short review is meant to provide background and guidance to the clinician and not to be exhaustive in discussing either environmental risk factors or genetics in AMD. Although absolute answers to determining risk of AMD are not yet available, this information may provide greater insight.

It has been determined recently that a common mutation in complement factor H (CFH), a protein that dampens the alternative pathway of complement activation, is highly associated with increased risk of AMD, both exudative and atrophic.^3,6,7 Further evidence supports that defects in the alternative pathway of complement activation are associated with AMD. Factor B mutations confer protection¹⁰, whereas Factor C3 mutations also impart risk.¹¹ CFH is one of the complement regulatory proteins that reduce activation of complement pathways, which result in the common end-product, the membrane attack complex (MAC). Traditionally, MAC is known to cause necrosis of cells, but it is now known that there are sublytic effects of MAC that can alter cell function. How would we interpret these findings in AMD? It appears that mutations would prevent the natural dampening of the alternative pathway by regulatory proteins and may tip the balance between expected aging to pathology in certain genetically susceptible patients or those exposed to environmental factors over time. However, for development of MAC to occur, complement must be present and activated. Drusen are composed of complement factors.¹² Research supports that photo-oxidative damage¹³ and certain infectious agents^14,15 are ways that complement can be activated to affect the eye or ocular cells. So this line of thinking helps resolve how a disease that has a strong association with genotype could occur late in life.

Environmental factors play a role too. Besides increased age, the most important risk factors reported are smoking and body mass index.^1,2 Some other risk factors
include low levels of carotenoids in the serum, blue light exposure, oxidative stress and inflammation.^16-22 Both smoking and body mass index can increase the risk of AMD over that present from genotype.²³

Although we know that inhibiting the bioactivity of vascular endothelial growth factor (VEGF) can help neovascular AMD patients with varying risk factor profiles,²⁴ we do not know if the efficacy of anti-VEGF treatments is associated with genotype. How is it possible that patients with multiple different risk factor profiles could receive benefit from anti-VEGF treatment? Many of the environmental risk factors for AMD have been shown in the laboratory to cause an increase in VEGF production in cells or animal models,^15,25,26 so inhibiting VEGF may have broad benefit. Yet only approximately 40% of patients with neovascular AMD receive significant visual acuity benefit from anti-VEGF agents.²⁴  Bioavailability and different mechanisms of action of drugs may differ as can the stage in disease pathogenesis when patients are treated. But recent evidence helps to provide additional clues. Studies have found associations of AMD with the untranslated regions of the VEGF gene.²⁷ These regions were not considered important in the past, but we now recognize that these are where factors may bind to initiate, interrupt or inhibit gene transcription and may help explain why some patients with multiple risk factors do not develop severe disease, whereas others with few risk factors do. In addition, evidence from animal models suggests that the outcome of VEGF inhibition may depend on the composition of the extracellular membrane/ Bruch’s.membrane.²⁸ 

The roles of both environmental risk factors and genotype are important in assessing risk of AMD. Environmental risk factors, particularly smoking and body mass index, increase the risk of AMD over that of genotype alone. Therefore, it is important to recommend that patients - regardless of genotype - reduce these risk factors. VEGF is important in the pathology of AMD regardless of risk profile but new findings of genetic mutations in the untranslated portion of the gene provide insight as to why some individuals with an apparently low risk profile develop disease whereas others with an apparently higher risk profile do not.

REFERENCES

1. Seddon, J. M., George, S., & Rosner, B. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration. Arch.Ophthalmol. 124, 995-1001 (2006).
2. Seddon, J. M., Willett, W. C., Speizer, F. E., & Hankinson, S. E. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 276, 1141-1146 (1996).
3. Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385-389 (2005).
4. Maller, J. et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat.Genet. 38, 1055-1059 (2006).
5. Li, M. et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 38, 1049-1054 (2006).
6. Haines, J. L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419-421 (2005).
7. Edwards, A. O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421-424 (2005).
8. Rivera, A. et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 14, 3227-3236 (2005).
9. Seddon, J. M., George, S., Rosner, B., & Klein, M. L. CFH Gene Variant, Y402H, and Smoking, Body Mass Index, Environmental Associations with Advanced Age-Related Macular Degeneration. Hum.Hered. 61, 157-165 (2006).
10. Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat.Genet. 38, 458-462 (2006).
11. Yates, J. R. W. et al. Complement C3 Variant and the Risk of Age-Related Macular Degeneration. N Engl J Med 357, 553-561 (2007).
12. Hageman, G. S. et al. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog.Retin.Eye Res. 20, 705-732 (2001).
13. Zhou, J., Jang, Y. P., Kim, S. R., & Sparrow, J. R. Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. PNAS 103, 16182-16187 (2006).
14. Robman, L. et al. Exposure to Chlamydia pneumoniae infection and progression of age-related macular degeneration. Am.J Epidemiol. 161, 1013-1019 (2005).
15. Kalayoglu, M. V. et al. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. Graefes Arch.Clin.Exp.Ophthalmol. 243, 1080-1090 (2005).
16. Seddon, J. M., Gensler, G., Milton, R. C., Klein, M. L., & Rifai, N. Association between C-reactive protein and age-related macular degeneration. JAMA 291, 704-710 (2004).
17. Eye Disease Case Control Study Group. Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol. 110, 1701-1708 (1992).
18. 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 119, 1417-1436 (2001).
19. Margrain, T. H., Boulton, M., Marshall, J., & Sliney, D. H. Do blue light filters confer protection against age-related macular degeneration? Prog Retin Eye Res 23, 523-531 (2004).
20. Espinosa-Heidmann, D. G. et al. Cigarette smoke-related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD. Invest Ophthalmol.Vis.Sci. 47, 729-737 (2006).
21. Despriet, D. D. et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 296, 301-309 (2006).
22. Shankar, A., Mitchell, P., Rochtchina, E., Tan, & Wang, J. J. Association between Circulating White Blood Cell Count and Long-Term Incidence of Age-related Macular Degeneration: The Blue Mountains Eye Study. Am J Epidemiol 165, 375-382 (2007).
23. Seddon, J. M. et al. Association of CFH Y402H and LOC387715 A69S With Progression of Age-Related Macular Degeneration. J Am Med Assoc 297, 1793-1800 (2007).
24. Rosenfeld, P. J. et al. Ranibizumab for Neovascular Age-Related Macular Degeneration. N Engl J Med 355, 1419-1431 (2006).
25. Grossniklaus, H. E. et al. Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 8, 119-126 (2002).
26. Zubilewicz, A. et al. Two distinct signalling pathways are involved in FGF2-stimulated proliferation of choriocapillary endothelial cells: A comparative study with VEGF. Oncogene 20, 1403-1413 (2001).
27. Churchill, A. J. et al. VEGF polymorphisms are associated with neovascular age-related macular degeneration. Hum Mol Genet 15, 2955-2961 (2006).
28. Nozaki, M. et al. Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J Clin Invest 116, 422-429 (2006).