Age-related macular degeneration (AMD) is a potentially blinding disease that affects older adults. It is estimated that by the year 2020 almost 200 million individuals will be affected by this condition worldwide.1 Currently, 30% of Americans ≥ 75 years of age have AMD.2 The yearly cost for health care due to AMD in the United States is $255 billion which is almost half of the direct cost for all vision loss in the United States.1 The etiology of this disease is multifactorial, involving a complex interaction of inflammatory, oxidative, degenerative and genetic components. Recent developments in the field of human genomics have fostered advancements in our knowledge of the genetic basis of AMD.
Prior to 2005, understanding of the heritability of AMD was limited and based largely on familial aggregation studies. These studies confirmed that a family history of AMD increases one’s risk for the development of the disease, and first-degree relatives of affected patients have a four-fold increased risk of developing the condition. In addition, monozygotic twins are known to have a high level of concordance for AMD compared to dizygotic twins.3-6
In 2005, a new era dawned with the completion of the International Haplotype Map Project which compiled a collection of millions of single nucleotide polymorphisms (SNP), normal variations in gene structure that may protect against or predispose to various conditions. Genome-wide association studies (GWAS) in large cohorts have identified many susceptibility loci associated with increased AMD risk, with complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) explaining more than 50% or greater of AMD heritability.7
The largest GWAS performed to date was conducted by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC), which is composed of 27 research groups and sponsored by the National Eye Institute. The IAMDGC analyzed genetic data of 16,144 patients with advanced AMD, 6,657 patients with intermediate AMD and 17,832 controls and identified 52 relevant variants spanning 34 loci.7
This year, the IAMDGC evaluated AMD genetic overlap with systemic disease. The group computed genetic risk scores for 60 diseases and traits and examined those associated with AMD using data from more than 33,000 participants. Associations of genetic risk scores of 16 different diseases/traits with AMD were identified including autoimmune diseases, cardiovascular disease, lipid health and bone density. Several genetic risk scores were related to ocular diseases including primary open angle glaucoma and myopia. Twenty-eight AMD-associated variants were also identified.8
The identification of relevant SNPs in GWAS allows us to focus our research efforts on the most relevant biologic pathways in AMD pathogenesis: complement activation, extracellular matrix (ECM) modulation, lipid transport, oxidative stress and angiogenesis.
Complement factor H SNP Y402H (rs1061170) on chromosome 1q32 was the first major susceptibility gene discovered for AMD and could be responsible for up to 50% of AMD risk. The CFH gene codes for a glycoprotein that regulates the alternative complement pathway and binds to Bruch’s membrane. The Y402H SNP can result in abnormal complement activation and host cell destruction secondary to ineffective binding to Bruch’s membrane. Complement factor H SNP Y402H promotes the development of early AMD (drusen formation) and progression to advanced AMD, and can act synergistically with smoking history to increase one’s risk of wet AMD.9-11
Various SNPs in the complement factor I (CFI), CFB/C2 and complement component 3 (C3) genes also promote complement activation and increase AMD risk.12-14 Bruch’s membrane is a specialized extracellular matrix located between the retinal pigment epithelium (RPE) and choroid that undergoes continuous remodeling and performs various signaling, barrier and filtering functions. It is composed of structural and matricellular proteins and growth factors. Remodeling is regulated by matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). SNPs in EFEMP1, HTRA1 and TIMP3 lead to MMP/TIMP imbalance and dysregulation of extracellular matrix remodeling, which promotes drusen and choroidal neovascular membrane formation.15
In 2013, Curcio et al reported the 2-lesion 2-compartment hypothesis to explain the role of lipid transport in drusen and subretinal drusenoid deposit formation.16 This hypothesis suggests that subretinal drusenoid deposits are a sign of RPE lipid recycling pathways resulting in a lipid and protein spill into the subretinal space, with subsequent photoreceptor damage and, ultimately, geographic atrophy.17 Relevant AMD-associated SNPs in the APOE, CETP and LIPC genes have been confirmed by the 2016 GWAS.18
ARMS2 was the second major susceptibility locus identified for AMD and is thought to mediate oxidative stress. ARMS2 risk alleles could compromise the response of superoxide dismutase 2, thereby increasing RPE vulnerability to oxidative stress. Homozygosity for ARMS2 high-risk polymorphisms confers increased risk for AMD progression and earlier onset of wet AMD.19
Vascular endothelial growth factor promotes endothelial cell migration, proliferation and angiogenesis. A recent meta-analysis by Barchitta et al identified three VEGF polymorphisms with a significant association with AMD.20
Greater understanding of this multifactorial disease advances the possibility of personalized medicine. The use of genetic testing has not yet been proven to improve outcomes and is not yet recommended for routine clinical use by the American Academy of Ophthalmology.21 Genotype has also been examined with respect to response to treatment with inconsistent results.1 Relevant SNP identification is paving the way for AMD gene therapy, but, at present, vectors are only in early stage clinical trials.
During the past few years, great strides have been made with respect to the understanding of the complex and polygenic basis of AMD. This knowledge has provided the foundation for genetic testing and the potential for gene-guided treatment and gene therapy.
1. DeAngelis MM, Owen LA, Morrison MA, et al. Genetics of age-related macular degeneration (AMD). Hum Mol Genet. 2017;26(R1):R45-R50.
2. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99(6):933-943.
3. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol. 1997 Feb;123(2):199-206.
4. Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT. Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol. 1998 Dec;116(12):1646-1651.
5. Klein BE, Klein R, Lee ME, Moore EL, Danforth L. Risk of incident age-related eye diseases in people with an affected sibling: The Beaver Dam Eye Study. Am J Epidemiol. 2001 Aug 1;154(3):207-211.
6. Meyers SM. A twin study on age-related macular degeneration. Trans Am Ophthalmol Soc. 1994;92:775-843.
7. Fritsche LG, Igi W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134-143.
8. Grassmann F, Kiel C, Zimmerman ME, et al. International Age-related Macular Degeneration Genomics Consortium (IAMDGC). Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. Genome Med. 2017 Mar 27;9(1):29.
9. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227-7232.
10. Clark SJ, Bishop PN, Day AJ. Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem Soc Trans. 2010 Oct;38(5):1342-1348.
11. Donoso LA, Vrabec T, Kuivaniemi H. The role of complement factor H in age-related macular degeneration: a review. Surv Ophthalmol. 2010 May-June;55(3);227-246.
12. Zipfel PH, Lauer N, Skerka C. The role of complement in AMD. Adv Exp Med Biol. 2010;703:9-24
13. Gehrs KM, Jackson JR, Brown EN, allikmets R, Hageman GS. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol. 2010 Mar;128(3):349-358.
14. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458-462.
15. Fernandez-Godino R, Pierce EA, Garland DL. Extracellular matrix alterations and deposit formation in AMD. Adv Exp Med Biol. 2016;854:53-58.
16. Curcio CA, Messinger JS, Sloan KR, McGwin G, Medeiros NE, Spaide RF. Subretinal drusenoid deposits in non-neovascular age-related macular degeneration: morphology, prevalence, topography, and biogenesis model. Retina. 2013;33:265-276.
17. Marsiglia M, Boddu S, Bearelly S, et al. Association between geographic atrophy progression and reticular pseudodrusen in eyes with dry age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013 Nov;54(12):7362-7369.
18. Pikuleva IA, Curcio CA. Cholesterol in the retina: the best is yet to come. Prog Retin Eye Res. 2014 July;41:64-89.
19. Rivera A, Fisher SA, Fritsche LG, 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. 2005;14:3227-3236.
20. Barchitta M, Maugeri A. Association between vascular endothelial growth factor polymorphisms and age-related macular degeneration: an updated meta-analysis. Dis Markers. 2016;2016:8486406.
21. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012 Nov;119(11):2408-2410.
About our author(s):
Jaclyn L. Kovach, MD is an Associate Professor of Ophthalmology at Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. She specializes in degenerative and vascular macular and retinal diseases.