Mechanisms of age-related macular degeneration and therapeutic opportunities

Journal of Pathology

Volumn 232, Issue 2, 2014, Pages 151-164

  Van Lookeren Campagne, Menno ^a   Lecouter, Jennifer ^a   Yaspan, Brian L ^a   Ye, Weilan ^a  

^a GENENTECH INC   (United States)

Author keywords

age related macular degeneration (AMD); best corrected visual acuity (BCVA); choroidal neovascularization (CNV); dry AMD; geographic atrophy (GA); neovascular AMD (NVAMD); retinal pigmented epithelial (RPE) cells; wet AMD

Indexed keywords

ACUTE PHASE PROTEIN; AFLIBERCEPT; ALTERNATIVE COMPLEMENT PATHWAY C3 C5 CONVERTASE; APOLIPOPROTEIN E; BEVACIZUMAB; CHOLESTEROL ESTER TRANSFER PROTEIN; COMPLEMENT COMPONENT C2; COMPLEMENT COMPONENT C3; COMPLEMENT FACTOR H; COMPLEMENT FACTOR I; COMPLEMENT MEMBRANE ATTACK COMPLEX; DECAY ACCELERATING FACTOR; IMMUNOGLOBULIN G; LIVER TRIACYLGLYCEROL LIPASE; MALONALDEHYDE; MANNOSE BINDING LECTIN; MONOCARBOXYLATE TRANSPORTER 3; PEGATINIB SODIUM; RAD51 B PROTEIN; RAD51 PROTEIN; RANIBIZUMAB; SCLEROPROTEIN; TISSUE INHIBITOR OF METALLOPROTEINASE 3; UNCLASSIFIED DRUG; VASCULOTROPIN A; VASCULOTROPIN INHIBITOR;

ALTERNATIVE MEDICINE; ANGIOGENESIS; APOPTOSIS; BLOOD VESSEL PERMEABILITY; BRUCH MEMBRANE; CHOROID CAPILLARY LAYER; COMPLEMENT ACTIVATION; COMPLEMENT FIXATION; DIZYGOTIC TWINS; ELECTRORETINOGRAPHY; FLUORESCENCE ANGIOGRAPHY; FOOD AND DRUG ADMINISTRATION; GENE LOCUS; GENETIC LINKAGE; GENETIC RISK; GENETIC VARIABILITY; GEOGRAPHIC ATROPHY; HEREDITY; HUMAN; LASER COAGULATION; LIPID METABOLISM; LIPID PEROXIDATION; MOLECULAR PATHOLOGY; MONOZYGOTIC TWINS; NEOVASCULAR AGE RELATED MACULAR DEGENERATION; NERVE CELL; NONHUMAN; OPTICAL COHERENCE TOMOGRAPHY; OXIDATIVE STRESS; PHASE 3 CLINICAL TRIAL (TOPIC); PHOTORECEPTOR CELL; PHOTORECEPTOR OUTER SEGMENT; PIGMENT EPITHELIUM; POLYPOIDAL CHOROIDAL VASCULOPATHY; PRIORITY JOURNAL; RETINA AMACRINE CELL; RETINA BLOOD VESSEL; RETINA DETACHMENT; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; RISK FACTOR; SIBLING RELATION; SIGNAL TRANSDUCTION; SUBRETINAL NEOVASCULARIZATION; TREATMENT DURATION; VISUAL ACUITY; VISUAL IMPAIRMENT;

AGE-RELATED MACULAR DEGENERATION (AMD); BEST CORRECTED VISUAL ACUITY (BCVA); CHOROIDAL NEOVASCULARIZATION (CNV); DRY AMD; GEOGRAPHIC ATROPHY (GA); NEOVASCULAR AMD (NVAMD); RETINAL PIGMENTED EPITHELIAL (RPE) CELLS; WET AMD;

ANIMALS; DISEASE MODELS, ANIMAL; DRUG DISCOVERY; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MACULAR DEGENERATION; MOLECULAR TARGETED THERAPY; PHENOTYPE; RETINA;

EID: 84890275820     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.4266     Document Type: Review

References (140)

1. Bressler NM, Bressler SB, Fine SL,. Age-related macular degeneration. Surv Ophthalmol 1988; 32: 375-413.
2. Muller H., Untersuchungen über die Glashäute des Auges, insbesondere die Glaslamelle der Chorioidea und ihre senilen Veränderungen. Graefes Arch Clin Exp Ophthalmol 1856; 2: 1-69.
3. Garron LK,. The ultrastructure of the retinal pigment epithelium with observations on the choriocapillaris and Bruch's membrane. Trans Am Ophthalmol Soc 1963; 61: 545-588.
4. Hayreh SS,. Segmental nature of the choroidal vasculature. Br J Ophthalmol 1975; 59: 631-648.
5. Ohkuma H, Ryan SJ,. Vascular casts of experimental subretinal neovascularization in monkeys. Invest Ophthalmol Vis Sci 1983; 24: 481-490.
6. Kohler T, Leiser R,. Blood vessels of the bovine chorioidea. A scanning electron microscopic study. Acta Anat (Basel) 1983; 116: 55-61.
7. McLeod DS, Lutty GA,. High-resolution histologic analysis of the human choroidal vasculature. Invest Ophthalmol Vis Sci 1994; 35: 3799-3811.
8. Motaghiannezam R, Schwartz DM, Fraser SE,. In vivo human choroidal vascular pattern visualization using high-speed swept-source optical coherence tomography at 1060 nm. Invest Ophthalmol Vis Sci 2012; 53: 2337-2348.
9. Bill A, Sperber G, Ujiie K,. Physiology of the choroidal vascular bed. Int Ophthalmol 1983; 6: 101-107.
10. Nickla DL, Wallman J,. The multifunctional choroid. Prog Retin Eye Res 2010; 29: 144-168.
11. Kur J, Newman EA, Chan-Ling T,. Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease. Prog Retin Eye Res 2012; 31: 377-406.
12. Chan-Ling T, Koina ME, McColm JR, et al., Role of CD44+ stem cells in mural cell formation in the human choroid: evidence of vascular instability due to limited pericyte ensheathment. Invest Ophthalmol Vis Sci 2011; 52: 399-410.
13. Condren AB, Kumar A, Mettu P, et al., Perivascular mural cells of the mouse choroid demonstrate morphological diversity that is correlated to vasoregulatory function. PLoS One 2013; 8: e53386.
14. Friedman DS, O'Colmain BJ, Munoz B, et al., Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564-572.
15. Klein R, Klein BE, Knudtson MD, et al., Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology 2007; 114: 253-262.
16. Bressler NM, Doan QV, Varma R, et al., Estimated cases of legal blindness and visual impairment avoided using ranibizumab for choroidal neovascularization: non-Hispanic white population in the United States with age-related macular degeneration. Arch Ophthalmol 2011; 129: 709-717.
17. Bird AC, Bressler NM, Bressler SB, et al., An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 1995; 39: 367-374.
18. Schneider U, Gelisken F, Inhoffen W,. Natural course of occult choroidal neovascularization in age-related macular degeneration: development of classic lesions in fluorescein angiography. Acta Ophthalmol Scand 2005; 83: 141-147.
19. Grossniklaus HE, Gass JD,. Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes. Am J Ophthalmol 1998; 126: 59-69.
20. Hermans P, Lommatzsch A, Bomfeld N, et al., [ Angiographic-histological correlation of late exudative age-related macular degeneration ]. Ophthalmologe 2003; 100: 378-383.
21. Liu TY, Shah AR, Del Priore LV,. Progression of lesion size in untreated eyes with exudative age-related macular degeneration a meta-analysis using Lineweaver-Burk plots. JAMA Ophthalmol 2013; 131: 335-340.
22. Ambati J, Fowler BJ,. Mechanisms of age-related macular degeneration. Neuron 2012; 75: 26-39.
23. Killingsworth MC,. Angiogenesis in early choroidal neovascularization secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 1995; 233: 313-323.
24. Mullins RF, Johnson MN, Faidley EA, et al., Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 2011; 52: 1606-1612.
25. Kornzweig AL,. Changes in the choriocapillaris associated with senile macular degeneration. Ann Ophthalmol 1977; 9: 753-756, 759-762.
26. Sarks JP, Sarks SH, Killingsworth MC,. Morphology of early choroidal neovascularisation in age-related macular degeneration: correlation with activity. Eye 1997; 11: 515-522.
27. Kwak N, Okamoto N, Wood JM, et al., VEGF is major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci 2000; 41: 3158-3164.
28. Campa C, Kasman I, Ye W, et al., Effects of an anti-VEGF-A monoclonal antibody on laser-induced choroidal neovascularization in mice: optimizing methods to quantify vascular changes. Invest Ophthalmol Vis Sci 2008; 49: 1178-1183.
29. Bhutto IA, McLeod DS, Hasegawa T, et al., Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration. Exp Eye Res 2006; 82: 99-110.
30. Frank RN, Amin RH, Eliott D, et al., Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol 1996; 122: 393-403.
31. Kvanta A, Algvere PV, Berglin L, et al., Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 1996; 37: 1929-1934.
32. Lopez PF, Sippy BD, Lambert HM, et al., Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 1996; 37: 855-868.
33. Lally DR, Gerstenblith AT, Regillo CD,. Preferred therapies for neovascular age-related macular degeneration. Curr Opin Ophthalmol 2012; 23: 182-188.
34. Frampton JE,. Ranibizumab a review of its use in the treatment of neovascular age-related macular degeneration. Drugs Aging 2013; 30: 331-358.
35. Thomas M, Mousa SS, Mousa SA,. Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration. Clin Ophthalmol 2013; 7: 495-501.
36. Querques G, Tran TH, Forte R, et al., Anatomic response of occult choroidal neovascularization to intravitreal ranibizumab a study by indocyanine green angiography. Graefes Arch Clin Exp Ophthalmol 2012; 250: 479-484.
37. Tran TH, Querques G, Forzy G, et al., Angiographic regression patterns after intravitreal ranibizumab injections for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2011; 42: 498-508.
38. Ryan S., The development of an experimental model of subretinal neovascularization in disciform macular degeneration. Trans Am Ophthalmol Soc 1979; 77: 707-745.
39. Dobi E, Puliafito C, Destro M,. A new model of experimental choroidal neovascularization in the rat. Arch Ophthalmol 1989; 107: 264-269.
40. Tobe T, Ortega S, Luna J, et al., Targeted disruption of the FGF2 gene does not prevent choroidal neovasculariation in a murine model. Am J Pathol 1998; 153: 1641-1646.
41. Miller H, Miller B, Ishibashi T, et al., Pathogenesis of laser-induced choroidal subretinal neovascularization. Invest Ophthalmol Vis Sci 1990; 31: 899-908.
42. Miller J, Adamis A, Shima D, et al., Vascular endothelial growth factor/vascular permeability factor is temporally and spatially corrrelated with ocular angiogenesis in a primate model. Am J Pathol 1994; 145: 574-584.
43. Yu L, Wu X, Cheng Z, et al., Interaction between bevacizumab and murine VEGF-A a reassessment. Invest Ophthalmol Vis Sci 2008; 49: 522-527.
44. Cao J, Zhao L, Li Y, et al., A subretinal Matrigel rat choroidal neovascularization (CNV) model and inhibition of CNV and associated inflammation and fibrosis by VEGF Trap. Invest Ophthalmol Vis Sci 2010; 51: 6009-6017.
45. Espinosa-Heidmann D, Suner I, Hernandez E, et al., Age as an independent risk factor for severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 2002; 43: 1567-1573.
46. Edelman J, Castro M,. Quantitative image analysis of laser-induced choroidal neovascularization in rat. Exp Eye Res 2000; 71: 523-533.
47. Kuroki A, Bhutto I, Kitaoka T, et al., Natural course of experimental choroidal neovascularization: three dimensional study with corrosion cast and scanning electron microscope. Ophthalmic Res 2002; 34: 200-205.
48. Cui JZ, Kimura H, Spee C, et al., Natural history of choroidal neovascularization induced by vascular endothelial growth factor in the primate. Graefes Arch Clin Exp Ophthalmol 2000; 238: 326-333.
49. Lassota N, Kiilgaard J, Prause J, et al., Surgical induction of choroidal neovascularization in a porcine model. Graefes Arch Clin Exp Ophthalmol 2007; 245: 1189-1198.
50. Lassota N, Prause J, Scherfig E, et al., Clinical and histological findings after intravitreal injection of bevacizumab (Avastin) in a porcine model of choroidal neovascularization. Acta Ophthalmol 2010; 88: 300-308.
51. Frykman P, Brown MS, Yamamoto T, et al., Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc Natl Acad Sci U S A 1995; 92: 8453-8457.
52. Heckenlively J, Hawes N, Friedlander M, et al., Mouse model of subretinal neovascularization with choroidal anastomosis. Retina 2003; 23: 518-522.
53. Yannuzzi L, Negrão S, Iida T, et al., Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001; 21: 416-434.
54. Slakter J, Yannuzzi L, Schneider U, et al., Retinal choroidal anastomoses and occult choroidal neovascularization in age-related macular degeneration. Ophthalmology 2000; 107: 742-753.
55. Yannuzzi L, Ciardella A, Spaide R, et al., The expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol 1997; 115: 478-485.
56. Jones A, Kumar S, Zhang N, et al., Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc Natl Acad Sci U S A 2011; 108: 14578-14583.
57. Ciardella A, Donsoff I, Huang S, et al., Polypoidal choroidal vasculopathy. Surv Ophthalmol 2004; 49: 25-37.
58. Sho K, Takahashi K, Yamada H, et al., Polypoidal choroidal vasculopathy: incidence, demographic features and clinical characteristics. Arch Ophthalmol 2003; 121: 1392-1396.
59. Ishida S, Usui T, Yamashiro K, et al., VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 2003; 198: 483-489.
60. Chen Y, Wiesmann C, Fuh G, et al., Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen. J Mol Biol 1999; 293: 865-881.
61. Lien S, Lowman HB,. Therapeutic anti-VEGF antibodies. Handb Exp Pharmacol 2008; 181: 131-150.
62. Holash J, Davis S, Papadopoulos N, et al., VEGF-Trap a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002; 99: 11393-11398.
63. Freund KB, Mrejen S, Gallego-Pinazo R,. An update on the pharmacotherapy of neovascular age-related macular degeneration. Expert Opin Pharmacother 2013; 14: 1017-1028.
64. Heier JS, Brown DM, Chong V, et al., Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 2012; 119: 2537-2548.
65. Ribatti D., The controversial role of placental growth factor in tumor growth. Cancer Lett 2011; 307: 1-5.
66. Li X, Kumar A, Zhang F, et al., Complicated life, complicated VEGF-B. Trends Mol Med 2012; 18: 119-127.
67. Papadopoulos N, Martin J, Ruan Q, et al., Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012; 15: 171-185.
68. Wang X, Yang J,. Analysis of the binding affinity of vascular endothelial growth factor A (VEGF) to ranibizumab, aflibercept and bevacizumab. ARVO (The Association for Research in Vision and Ophthalmology) Annual Meeting Abstracts 2013; Session 255: 10-11.
69. Lanzetta P, Mitchell P, Wolf S, et al., Different antivascular endothelial growth factor treatments and regimens and their outcomes in neovascular age-related macular degeneration a literature review. Br J Ophthalmol 2013; DOI: 10.1136/bjophthalmol-2013-303394 (in press).
70. Rosenfeld PJ, Shapiro H, Tuomi L, et al., Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials. Ophthalmology 2011; 118: 523-530.
71. Boyer DS, Antoszyk AN, Awh CC, et al., Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007; 114: 246-252.
72. Kaiser PK, Brown DM, Zhang K, et al., Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol 2007; 144: 850-857.
73. Kang S, Roh YJ,. One-year results of intravitreal ranibizumab for neovascular age-related macular degeneration and clinical responses of various subgroups. Jpn J Ophthalmol 2009; 53: 389-395.
74. Ying GS, Huang J, Maguire MG, et al., Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration. Ophthalmology 2013; 120: 122-129.
75. Lindahl P, Johansson BR, Leveen P, et al., Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997; 277: 242-245.
76. Hellstrom M, Kalen M, Lindahl P, et al., Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999; 126: 3047-3055.
77. Lindblom P, Gerhardt H, Liebner S, et al., Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 2003; 17: 1835-1840.
78. Jo N, Mailhos C, Ju M, et al., Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006; 168: 2036-2053.
79. Mitchell TS, Bradley J, Robinson GS, et al., RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis 2008; 11: 141-151.
80. Jayson GC, Parker GJ, Mullamitha S, et al., Blockade of platelet-derived growth factor receptor-beta by CDP860 a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume. J Clin Oncol 2005; 23: 973-981.
81. Serruys PW, Heyndrickx GR, Patel J, et al., Effect of an anti-PDGF-beta-receptor-blocking antibody on restenosis in patients undergoing elective stent placement. Int J Cardiovasc Intervent 2003; 5: 214-222.
82. Klein R, Meuer SM, Knudtson MD, et al. The epidemiology of retinal reticular drusen. Am J Ophthalmol 2008; 145: 317-326.
83. Sparrow JR, Zhou J, Cai B,. DNA is a target of the photodynamic effects elicited in A2E-laden RPE by blue-light illumination. Invest Ophthalmol Vis Sci 2003; 44: 2245-2251.
84. Cherepanoff S, McMenamin P, Gillies MC, et al., Bruch's membrane and choroidal macrophages in early and advanced age-related macular degeneration. Br J Ophthalmol 2010; 94: 918-925.
85. Ebrahimi KB, Handa JT,. Lipids, lipoproteins, and age-related macular degeneration. J Lipids 2011; 2011: 802059.
86. Ebrahimi KB, Fijalkowski N, Cano M, et al., Decreased membrane complement regulators in the retinal pigmented epithelium contribute to age-related macular degeneration. J Pathol 2013; 229: 729-742.
87. Heurich M, Martinez-Barricarte R, Francis NJ, et al., Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc Natl Acad Sci U S A 2011; 108: 8761-8766.
88. Miller YI, Choi SH, Wiesner P, et al., Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res 2011; 108: 235-248.
89. Weismann D, Hartvigsen K, Lauer N, et al., Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 2011; 478: 76-81.
90. Sparrow JR, Fishkin N, Zhou J, et al., A2E a byproduct of the visual cycle. Vision Res 2003; 43: 2983-2990.
91. Zhou J, Jang YP, Kim SR, et al., Complement activation by photooxidation products of A2E a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci U S A 2006; 103: 16182-16187.
92. Palczewska G, Maeda T, Imanishi Y, et al., Noninvasive multiphoton fluorescence microscopy resolves retinol and retinal condensation products in mouse eyes. Nature Med 2010; 16: 1444-1449.
93. Suter M, Reme C, Grimm C, et al., Age-related macular degeneration. The lipofusion component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem 2000; 275: 39625-39630.
94. Zeiss C., Review paper: animals as models of age-related macular degeneration: an imperfect measure of the truth. Vet Pathol 2010; 47: 396-413.
95. Ramkumar H, Zhang J, Chan C-C,. Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD). Prog Retin Eye Res 2010; 29: 169-190.
96. Pennesi ME, Neuringer M, Courtney RJ,. Animal models of age related macular degeneration. Mol Aspects Med 2012; 33: 487-509.
97. Wang AL, Neufeld AH,. Smoking mice a potential model for studying accumulation of drusen-like material on Bruch's membrane. Vision Res 2010; 50: 638-642.
98. Fujihara M, Nagai N, Sussan T, et al., Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice. PLoS One 2008; 3: e3119.
99. Wielgus A, Collier R, Martin E, et al., Blue light induced A2E oxidation in rat eyes-experimental animal model of dry AMD. Photochem Photobiol Sci 2010; 9: 1505-1512.
100. Ishibashi T, Sargente N, Patterson R, et al., Pathogenesis of drusen in the primate. Invest Ophthalmol Vis Sci 1986; 27: 184-193.
101. Dawson W, Dawson J, Lake K, et al., Maculas, monkeys, models, AMD and aging. Vision Res 2008; 48: 360-365.
102. Hope G, Dawson W, Engel H, et al., A primate model for age related macular drusen. Br J Ophthalmol 1992; 76: 11-15.
103. Evans JB, Syed BA,. New hope for dry AMD? Nature Rev Drug Discov 2013; 12: 501-502.
104. Klein ML, Mauldin WM, Stoumbos VD,. Heredity and age-related macular degeneration. Observations in monozygotic twins. Arch Ophthalmol 1994; 112: 932-937.
105. Meyers SM, Greene T, Gutman FA,. A twin study of age-related macular degeneration. Am J Ophthalmol 1995; 120: 757-766.
106. Seddon JM, Ajani UA, Mitchell BD,. Familial aggregation of age-related maculopathy. Am J Ophthalmol 1997; 123: 199-206.
107. Heiba IM, Elston RC, Klein BE, et al., Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol 1994; 11: 51-67.
108. Klaver CC, Wolfs RC, Assink JJ, et al., Genetic risk of age-related maculopathy. population-based familial aggregation study. Arch Ophthalmol 1998; 116: 1646-1651.
109. Seddon JM, Cote J, Page WF, et al., The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005; 123: 321-327.
110. Klein ML, Schultz DW, Edwards A, et al., Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol 1998; 116: 1082-1088.
111. Gorin MB,. Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics. Mol Aspects Med 2012; 33: 467-486.
112. Haines JL, Hauser MA, Schmidt S, et al., Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419-421.
113. 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: 7227-7232.
114. Edwards AO, Ritter R 3rd, Abel KJ, et al., Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421-424.
115. Klein RJ, Zeiss C, Chew EY, et al., Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385-389.
116. 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: 149-153.
117. Despriet DD, Klaver CC, Witteman JC, et al., Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. J Am Med Assoc 2006; 296: 301-309.
118. 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.
119. Jakobsdottir J, Conley YP, Weeks DE, et al., Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005; 77: 389-407.
120. Clark SJ, Perveen R, Hakobyan S, et al., Impaired binding of the age-related macular degeneration-associated complement factor H 402H allotype to Bruch's membrane in human retina. J Biol Chem 2010; 285: 30192-30202.
121. Wang G, Scott WK, Agarwal A, et al., Coding variants in ARMS2 and the risk of age-related macular degeneration. JAMA Ophthalmol 2013; 131: 804-805.
122. Yang Z, Tong Z, Chen Y, et al., Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS Genet 2010; 6: e1000836.
123. Hadley D, Orlin A, Brown G, et al., Analysis of six genetic risk factors highly associated with AMD in the region surrounding ARMS2 and HTRA1 on chromosome 10, region q26. Invest Ophthalmol Vis Sci 2010; 51: 2191-2196.
124. 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. Nature Genet 2006; 38: 458-462.
125. 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. Nature Genet 2006; 38: 1049-1054.
126. 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. Nature Genet 2006; 38: 1055-1059.
127. 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: 553-561.
128. Fagerness JA, Maller JB, Neale BM, et al., Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 2009; 17: 100-104.
129. 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.
130. Fritsche LG, Chen W, Schu M, et al., Seven new loci associated with age-related macular degeneration. Nature Genet 2013; 45: 433-439.
131. Klaver CC, Kliffen M, van Duijn CM, et al., Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998; 63: 200-206.
132. Souied EH, Benlian P, Amouyel P, et al., The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 1998; 125: 353-359.
133. McKay GJ, Patterson CC, Chakravarthy U, et al., Evidence of association of APOE with age-related macular degeneration a pooled analysis of 15 studies. Hum Mutat 2011; 32: 1407-1416.
134. 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.
135. 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: 7401-7406.
136. Sobrin L, Reynolds R, Yu Y, et al., ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration. Am J Ophthalmol 2011; 151: 345-352 e343.
137. Seddon JM, Francis PJ, George S, et al., Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. J Am Med Assoc 2007; 297: 1793-1800.
138. Raychaudhuri S, Iartchouk O, Chin K, et al., A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nature Genet 2011; 43: 1232-1236.
139. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS): design implications. AREDS report No. 1. Controlled Clin Trials 1999; 20: 573-600.
140. Davis MD, Gangnon RE, Lee LY, et al., The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol 2005; 123: 1484-1498.