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Genetic Basis of Age-related Macular Degeneration

Published Online: October 12th 2011 US Ophthalmic Review, 2011;4(2):119-21 DOI: http://doi.org/10.17925/USOR.2011.04.02.119
Authors: Mohammad Othman, Kari Branham, John R Heckenlively
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Abstract:
Overview

Age-related macular degeneration (AMD) is the main cause of vision loss and impairment in the aging population in developed countries. It is clinically and genetically a complex disease with both environmental and genetic factors affecting the outcome of the disease. Other than the wet type of AMD, there is no treatment for the other forms of AMD. It is estimated that the number of AMD patients will double in the next decade, which will have a significant financial impact on the health system and will compete for health dollars. Understanding the role of genetics in the development of AMD is paramount to help with diagnosis and future treatment. Over the past few years, we have studied the genetics of AMD and reported modest to significant association between AMD and several genes including CFH, ARMS2, TLR4 and ApoE. Our recent genome-wide association studies confirmed these AMD susceptibility loci in addition to other genes in the complement system (C2, C3, CFB and CFI). Recent studies identified new loci near TIMP3 and HDL influencing susceptibility to AMD.

Keywords

Age-related macular degeneration, genes, macular degeneration, susceptibility loci

Article:

Literature Review


Literature Review
Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the elderly population in the developed world. This major health problem is expected to worsen with the projected increase in numbers of the aging population. A full understanding of the pathobiology of the disease process is still elusive, and is compounded by the heterogeneous nature and complexity of the disease.1,2 Family history and linkage studies point toward a multigenic basis for AMD,3–5 including genetic factors which affect aging and mitochondrial contributions to aging.6–13 There are known environmental factors, such as diet, phototoxicity, smoking, drinking white wine (as opposed to red wine), and inflammatory insults to the retina, during the lifetime of patients that will contribute to an increased or decreased risk of developing disease.14–17 Currently, the contribution of inflammation and complement components to the pathology of AMD is generating new interest. Several reports have discussed the role of the immune system in AMD.18–24 Recently, a number of association studies identified sequence variants in the complement factor H (CFH) gene to be significantly associated with AMD.25–30 Other complement components and factors were shown to increase the risk of AMD.31–36

This article focuses on the genetic basis of macular degeneration and will discuss briefly the results of our reported studies, current studies, and plans for future studies. Our primary aim has been to identify the genes that cause or are intimately associated with the pathophysiology of AMD, which in turn identifies the pathways and processes underlying the development of AMD. Eventually, these studies will help develop drugs designed specifically to treat AMD, or to significantly delay the progress of AMD in the aging population.

Early genetic investigations into AMD worked to understand the familial contribution to disease and focused on twin studies and familial aggregation studies. Twin studies have demonstrated complete concordance (100 %) for both members of monozygotic twin pairs being affected with AMD and usually being affected with the same stage of disease.37–39 This can be compared with the data looking at dizygotic twin pairs, which showed a lower concordance (42–50 % ) for being affected with AMD.37,39 Similarly, familial aggregation studies have shown a higher prevalence of AMD among first-degree relatives of affected probands as compared with first-degree relatives of control probands.40,41 Results from these early studies demonstrated the useful role of family history in studying AMD, and paved the way for future genetic linkage and association studies.

Early association studies focused on genes that had been previously identified in diseases manifesting with similar retinal phenotypes to AMD (i.e. macular dystrophies). Association studies looking at the EFEMP1,42 ELOVL4,43 RDS,44 TIMP3,45 and VMD246,47 genes have yet to reveal strong associations in AMD patients. Although some early studies indicated an association of AMD with mutations in ABCA4,48,49 further studies did not demonstrate an association with this gene.50–52

Identification of susceptibility loci for AMD requires the application of classical genetic studies and more advanced genome-wide association studies (GWAS). The aims of these studies are to confirm the role of genetics in AMD and to identify genes that might cause AMD or be associated with the development of AMD. Several classical linkage studies were carried out using panels of markers spanning the entire chromosomes against AMD patients (families and sib-pairs).53–57 GWAS, using high-density single nucleotide polymorphism (SNP) chips, were used to precisely localize AMD-associated genes.28,58 In this article we will focus on the major loci identified by these studies.

Linkage Studies
We performed an association linkage analysis with high-density markers (5 cM) on 412 affected relative pairs, primarily affected with geographic atrophy and/or neovascularization.53 Our analysis confirmed earlier linkage studies data54,55,59 and identified other possible areas of interest for study. The first locus on chromosome 1q31 turned out to include CFH, a gene involved in regulating the function of C3 in the alternative complement pathway. Meta-analysis of various reported linkage studies identified several AMD loci.4 Furthermore, a recent review from our laboratory on the status of AMD and current genetic susceptibility studies had compiled the linkage loci and localized them to regions on different chromosomes.60 The results of the various linkage studies reflected the complexity and heterogeneity of AMD. However, there were two clear AMD association loci that were identified in several linkage analysis studies, located at 1q31 and 10q26.53–55

Sequence Variants in Candidate Genes and their Association with Age-related Macular Degeneration
Candidate genes for associated studies were selected based on knowledge of gene functions and/or information obtained from linkage studies. These genes were sequenced using our Michigan AMD cohort (over 850 cases and controls) to identify any sequence variants. Statistical analysis was done to compare the probabilities of the genotypes and alleles frequencies in both AMD cases and controls. Apolipoprotein E alleles were studied to determine if any of the alleles would be associated with AMD. The ApoE4 allele was shown to be protective from AMD, and was present in controls at a significantly higher frequency than in the AMD cases;61 also, our results confirmed findings which are in agreement with the findings of previous studies, with one difference, that our sample size was larger.62,63 The toll-like receptor 4 (TLR4) gene was investigated for a possible association with AMD due to the implication that inflammation and the complement system pathways are involved in AMD.21–23,64 This gene was selected because it is localized to 9q32-33, another locus found by our AMD association linkage studies. Furthermore, it was an attractive candidate as it is considered a proinflammatory gene.65,66 The D299G TLR4 sequence variant was shown to be significantly associated with AMD.67 Recently, we repeated an association study between AMD and SNPs in the toll-like receptor 3 (TLR3) and toll-like receptor 7 (TLR7) genes. In spite of our not finding an association between our AMD cases and these genes (analyzing 610 AMD patients and 324 controls), the SNPs in those genes were reported to be associated with AMD in another cohort.68 A recent analysis identified a protective role of a variant in the TLR3 gene against geographic atrophy.69 The TLR association remains open to further study.

1q32 and Complement Factor H
The identification of CFH on 1q32, as the first major AMD association locus, resulted from a genome-wide association study. The Y402H SNP was hailed as a significant finding because it related to increased risk of AMD and to the function of CFH. This change was predicted to alter the function of CFH and pointed to the role of complement components in the development of AMD.28 Several studies reported similar findings, with increased risk of AMD with the Y402H allele.25–27 We repeated the association study with CFH Y402H, using our large cohort of AMD cases and controls, and reported similar findings as the previous studies and showed that this risk allele is highly associated with AMD.30 We extended our CFH study identifying other SNPs that had a stronger association with AMD than the Y402H SNP. By examining 84 SNPs in the region of CFH, we found that several haplotypes that do not include Y402H had a stronger association with AMD than Y402H alone.29

The 10q26 Locus and Age-related Macular Degeneration
Several linkage studies have confirmed 10q26 to be a major AMD association locus.57,70,71 The region includes three nearby genes (PLEKHA1, LOC387715 and HTRA1). Reports showed that one SNP (rs11200638) in the promoter region of HTRA1 is highly associated with AMD.58,72 However, our work and the work of others has shown that the rs10490924 SNP, in the hypothetical gene LOC387715 (now known as ARMS2), has a stronger association with AMD than rs11200638.73–77 ARMS2 is of interest because it is only present in higher primates that have maculae (humans and chimpanzees). We reported that the ARMS2 gene protein is expressed and localized to the mitochondria of transfected cell lines.74 A recent study confirmed our findings by showing that the LOC387715 protein is expressed and localized to the mitochondria in photoreceptors.73 This study also identified a deletion/insertion in the 3’ end of ARMS2 that accelerates the decay of the mRNA. This may be one of the reasons why the protein and mRNA are not being expressed or detected in the mitochondria of AMD-affected individuals.73


Recent Studies
The genetics of AMD are complex and far more difficult to investigate compared with typical monogenic diseases. Identifying the various genetic loci that contribute to the AMD disease process will eventually be able to put the big picture together so we can start to understand the genetic pathways active in individual patients which are influencing them to develop AMD. To address this, we were involved in a multicenter study with over 3,000 AMD cases and controls in an attempt to find new loci as part of a new GWAS consortium using the Illumina Human370 bead chips and the Illumina Infinium II assay protocol. Our GWAS data were published recently,78 where we confirmed the earlier findings for the two major susceptibility loci (CFH and ARMS2), in addition to the other loci for C2/CFB, C3, and CFI. This comprehensive study identified additional susceptibility loci with genetic variants near the regions of TIMP3 and HDL-associated loci. When this study looked at all susceptibility loci, 329/331 (99 % ) cases were identified and 85 % of them had advanced AMD. Future work is needed to verify the role of these genes in the diagnosis, development, progression, and treatment of AMD.

Article Information:
Disclosure

This research was supported by grants from the NEI/NIH (R01 EY016862), NEI/NIH Core Center for Vision Research (P30 EY07003), Foundation Fighting Blindness, and the Elmer and Sylvia Sramek Foundation.

Correspondence

John R Heckenlively, MD, Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI, 48105, US. E: miothman@umich.edu

Received

2011-02-10T00:00:00

References

  1. Lotery A, Trump D, Progress in defining the molecular biology of age related macular degeneration, Hum Genet, 2007;122(3–4):219–36.
  2. Gehrs KM, Anderson DH, Johnson LV, Hageman GS, Age-related macular degeneration—emerging pathogenetic and therapeutic concepts, Ann Med, 2006;38(7):450–71.
  3. Haddad S, Chen CA, Santangelo SL, Seddon JM, The genetics of age-related macular degeneration: a review of progress to date, Surv Ophthalmol, 2006;51(4):316–63.
  4. Fisher SA, Abecasis JR, Yashar BM, et al., Meta-analysis of genome scans of age-related macular degeneration, Hum Mol Genet, 2005;14(15):2257–64.
  5. Swaroop A, Branham KE, Chen W, Abecasis G, Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits, Hum Mol Genet, 2007;16(Spec. 2):R174–82.
  6. Feher J, Kovacs I, Artico M, et al., Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration, Neurobiol Aging, 2006;27(7):983–93.
  7. Wallace DC, Brown MD, Melov S, et al., Mitochondrial biology, degenerative diseases and aging, Biofactors, 1998;7(3):187–90.
  8. Wallace DC, Mitochondrial defects in neurodegenerative disease, Ment Retard Dev Disabil Res Rev, 2001;7(3):158–66.
  9. Wallace DC, Mitochondrial diseases in man and mouse, Science, 1999;283(5407):1482–8.
  10. Wallace DC, Shoffner JM, Trounce I, et al., Mitochondrial DNA mutations in human degenerative diseases and aging, Biochim Biophys Acta, 1995;1271(1):141–51.
  11. Canter JA, Olson LM, Spencer K, et al., Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration, PLoS One, 2008;3(5):e2091.
  12. Wallace DC, A mitochondrial paradigm for degenerative diseases and ageing, Novartis Found Symp, 2001;235:247–63; discussion 263–6.
  13. Nordgaard CL, Karunadharma PP, Feng X, et al., Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration, Invest Ophthalmol Vis Sci, 2008;49(7):2848–55.
  14. Chiu CJ, Milton RC, Gensler G, Taylor A, Association between dietary glycemic index and age-related macular degeneration in nondiabetic participants in the Age-Related Eye Disease Study, Am J Clin Nutr, 2007;86(1):180–8.
  15. Klein ML, Francis PJ, Rosner B, et al., CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration, Ophthalmology, 2008;115(6):1019–25.
  16. Klein R, Knudtson MD, Cruickshanks KJ, Klein BE, Further observations on the association between smoking and the long-term incidence and progression of age-related macular degeneration: the Beaver Dam Eye Study, Arch Ophthalmol, 2008;126(1):115–21.
  17. Schmidt S, Hauser MA, Scott WK, et al., Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration, Am J Hum Genet, 2006;78(5):852–64.
  18. Nozaki M, Raisler BJ, Sakurai E, et al., Drusen complement components C3a and C5a promote choroidal neovascularization, Proc Natl Acad Sci U S A, 2006;103(7):2328–33.
  19. Dinu V, Miller PL, Zhao H, Evidence for association between multiple complement pathway genes and AMD, Genet Epidemiol, 2007;31(3):224–37.
  20. Penfold PL, Madigan MC, Gillies MC, Provis JM, Immunological and aetiological aspects of macular degeneration, Prog Retin Eye Res, 2001;20(3):385–414.
  21. Kanda A, Abecasis G, Swaroop A, Inflammation in the pathogenesis of age-related macular degeneration, Br J Ophthalmol, 2008;92(4):448–50.
  22. Klein R, Knudtson MD, Klein BE, et al., Inflammation, Complement Factor H, and Age-Related Macular Degeneration The Multi-Ethnic Study of Atherosclerosis, Ophthalmology, 2008;115(10):1742–9.
  23. McGeer EG, Klegeris A, McGeer PL, Inflammation, the complement system and the diseases of aging, Neurobiol Aging, 2005;26(Suppl. 1):94–7.
  24. Hageman GS, Luthert PJ, Victor Chong NH, 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, 2001;20(6):705–32.
  25. Edwards AO, Ritter R 3rd, Abel KJ, et al., Complement factor H polymorphism and age-related macular degeneration, Science, 2005;308(5720):421–4.
  26. Hageman GS, Anderson DH, Johnson LV, et al., A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration, Proc Natl Acad Sci U S A, 2005;102(20):7227–32.
  27. Haines JL, Hauser MA, Schmidt S, et al., Complement factor H variant increases the risk of age-related macular degeneration, Science, 2005;308(5720):419–21.
  28. Klein RJ, Zeiss C, Chew EY, et al., Complement factor H polymorphism in age-related macular degeneration, Science, 2005;308(5720):385–9.
  29. Li M, Atmaca-Sonmez P, Othman M, et al., CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration, Nat Genet, 2006;38(9):1049–54.
  30. Zareparsi S, Branham KE, Li M, et al., Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration, Am J Hum Genet, 2005;77(1):149–53.
  31. 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(4):458–62.
  32. Jakobsdottir J, Conley YP, Weeks DE, et al., C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes, PLoS One, 2008;3(5):e2199.
  33. Maller JB, Fagerness JA, Reynolds RC, et al., Variation in complement factor 3 is associated with risk of age-related macular degeneration, Nat Genet, 2007;39(10):1200–1.
  34. Sivaprasad S, Adewoyin T, Bailey TA, et al., Estimation of systemic complement C3 activity in age-related macular degeneration, Arch Ophthalmol, 2007;125(4):515–9.
  35. Spencer KL, Olson LM, Anderson BM, et al., C3 R102G polymorphism increases risk of age-related macular degeneration, Hum Mol Genet, 2008;17(12):1821–4.
  36. Yates JR, Sepp T, Matharu BK, et al., Complement C3 variant and the risk of age-related macular degeneration, N Engl J Med, 2007;357(6):553–61.
  37. Grizzard SW, Arnett D, Haag SL, Twin study of age-related macular degeneration, Ophthalmic Epidemiol, 2003;10(5):315–22.
  38. Klein ML, Mauldin WM, Stoumbos VD, Heredity and age-related macular degeneration. Observations in monozygotic twins, Arch Ophthalmol, 1994;112(7):932–7.
  39. Meyers SM, A twin study on age-related macular degeneration, Trans Am Ophthalmol Soc, 1994;92:775–843.
  40. Seddon JM, Ajani UA, Mitchell BD, Familial aggregation of age-related maculopathy, Am J Ophthalmol, 1997;123(2):199–206.
  41. Klaver CC, Wolfs RC, Assink JJ, et al., Genetic risk of age-related maculopathy. Population-based familial aggregation study, Arch Ophthalmol, 1998;116(12):1646–51.
  42. Stone EM, Lotery AJ, Munier FL, et al., A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy, Nat Genet, 1999;22(2):199–202.
  43. Ayyagari R, Zhang K, Hutchinson A, et al., Evaluation of the ELOVL4 gene in patients with age-related macular degeneration, Ophthalmic Genet, 2001;22(4):233–9.
  44. Baird PN, Richardson A, Islam A, et al., Analysis of the RDS/peripherin gene in age-related macular degeneration, Clin Experiment Ophthalmol, 2007;35(2):194–5.
  45. De La Paz MA, Pericak-Vance MA, Lennon F, et al., Exclusion of TIMP3 as a candidate locus in age-related macular degeneration, Invest Ophthalmol Vis Sci, 1997;38(6):1060–5.
  46. Allikmets R, Seddon JM, Bernstein PS, et al., Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies, Hum Genet, 1999;104(6):449–53.
  47. Lotery AJ, Munier FL, Fishman GA, et al., Allelic variation in the VMD2 gene in best disease and age-related macular degeneration, Invest Ophthalmol Vis Sci, 2000;41(6):1291–6.
  48. Allikmets R, Shroyer NF, Singh N, et al., Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration, Science, 1997;277(5333):1805–7.
  49. Allikmets R, Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium, Am J Hum Genet, 2000;67(2):487–91.
  50. Rivera A, White K, Stöhr H, et al., A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration, Am J Hum Genet, 2000;67(4):800–13.
  51. Schmidt S, Postel EA, Agarwal A, et al., Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy, Invest Ophthalmol Vis Sci, 2003;44(7):2868–75.
  52. Stone EM, Webster AR, Vandenburgh K, et al., Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration, Nat Genet, 1998;20(4):328–9.
  53. Abecasis GR, Yashar BM, Zhao Y, et al., Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease, Am J Hum Genet, 2004;74(3):482–94.
  54. Majewski J, Schultz DW, Weleber RG, et al., Age-related macular degeneration—a genome scan in extended families, Am J Hum Genet, 2003;73(3):540–50.
  55. Weeks DE, Conley YP, Tsai HJ, et al., Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions, Am J Hum Genet, 2004;75(2):174–89.
  56. Weeks DE, Conley YP, Tsai HJ, et al., Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions, Am J Ophthalmol, 2001;132(5):682–92.
  57. Kenealy SJ, Schmidt S, Agarwal A, et al., Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26, Mol Vis, 2004;10:57–61.
  58. Dewan A, Liu M, Hartman S, et al., HTRA1 promoter polymorphism in wet age-related macular degeneration, Science, 2006;314(5801):989–92.
  59. Seddon JM, Santangelo SL, Book K, et al., A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions, Am J Hum Genet, 2003;73(4):780–90.
  60. Swaroop A, Branham KE, Chen W, Abecasis G, Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits, Hum Mol Genet, 2007;16(Spec. 2):R174–82.
  61. Zareparsi S, Reddick AC, Branham KE, et al., Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center, Invest Ophthalmol Vis Sci, 2004;45(5):1306–10.
  62. Simonelli F, Margaglione M, Testa F, et al., Apolipoprotein E polymorphisms in age-related macular degeneration in an Italian population, Ophthalmic Res, 2001;33(6):325–8.
  63. Bojanowski CM, Shen D, Chew EY, et al., An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation, Environ Mol Mutagen, 2006;47(8):594–602.
  64. McGeer PL, McGeer EG, Inflammation and the degenerative diseases of aging, Ann N Y Acad Sci, 2004;1035:104–16.
  65. Zeuke S, Ulmer AJ, Kusumoto S, et al., TLR4-mediated inflammatory activation of human coronary artery endothelial cells by LPS, Cardiovasc Res, 2002;56(1):126–34.
  66. Kim F, Pham M, Luttrell I, et al., Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity, Circ Res, 2007;100(11):1589–96.
  67. Zareparsi S, Buraczynska M, Branham KE, et al., Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration, Hum Mol Genet, 2005;14(11):1449–55.
  68. Edwards AO, Chen D, Fridley BL, et al., Toll-like receptor polymorphisms and age-related macular degeneration, Invest Ophthalmol Vis Sci, 2008;49(4):1652–9.
  69. Yang Z, Stratton C, Francis PJ, et al., Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration, N Engl J Med, 2008;359(14):1456–63.
  70. Fisher SA, Rivera A, Fritsche LG, et al., Assessment of the contribution of CFH and chromosome 10q26 AMD susceptibility loci in a Russian population isolate, Br J Ophthalmol, 2007;91(5):576–8.
  71. 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(21):3227–36.
  72. Yang Z, Camp NJ, Sun H, et al., A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration, Science, 2006;314(5801):992–3.
  73. Fritsche LG, Loenhardt T, Janssen A, et al., Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA, Nat Genet, 2008;40(7):892–6.
  74. Kanda A, Chen W, Othman M, et al., A variant of mitochondrial protein LOC387715/ ARMS2, not HTRA1, is strongly associated with age-related macular degeneration, Proc Natl Acad Sci U S A, 2007;104(41):16227–32.
  75. Ross RJ, Bojanowski CM, Wang JJ, et al., The LOC387715 polymorphism and age-related macular degeneration: replication in three case-control samples, Invest Ophthalmol Vis Sci, 2007;48(3):1128–32.
  76. Schaumberg DA, Hankinson SE, Guo Q, et al., A prospective study of 2 major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors, Arch Ophthalmol, 2007;125(1):55–62.
  77. Seddon JM, Francis PJ, George S, et al., Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration, JAMA, 2007;297(16):1793–1800.
  78. Chen W, Stambolian D, Edwards AO, et al., Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration, Proc Natl Acad Sci U S A, 2010;107(16):7401–6.

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