Age-related macular degeneration: Genetic and clinical findings

Clinical Chemistry and Laboratory Medicine

Volumn 49, Issue 4, 2011, Pages 601-616

  Kokotas, Haris ^a   Grigoriadou, Maria ^a   Petersen, Michael B ^a  

^a AGHIA SOPHIA CHILDREN S HOSPITAL   (Greece)

Author keywords

age related macular degeneration; blindness; clinical signs; genes

Indexed keywords

ABC TRANSPORTER; ALTERNATIVE COMPLEMENT PATHWAY C3 C5 CONVERTASE; APOLIPOPROTEIN E; ATP BINDING CASSETTE, SUBFAMILY A, MEMBER 4; CHEMOKINE RECEPTOR CX3CR1; COMPLEMENT COMPONENT C2; COMPLEMENT COMPONENT C3; COMPLEMENT FACTOR H; COMPLEMENT FACTOR I; CYSTATIN C; ESTROGEN RECEPTOR ALPHA; FIBULIN 5; MITOCHONDRIAL DNA; TISSUE INHIBITOR OF METALLOPROTEINASE 3; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 4; TRIACYLGLYCEROL LIPASE; UNCLASSIFIED DRUG; VASCULOTROPIN;

BRUCH MEMBRANE; CHOROID; CLINICAL FEATURE; DATA BASE; ENVIRONMENTAL FACTOR; EXCISION REPAIR CROSS COMPLEMENTING GROUP 6 GENE; GENE; GENETIC ANALYSIS; GENETIC RISK; GENETIC SUSCEPTIBILITY; HEMICENTIN 1 GENE; HEREDITY; HTRA1 GENE; HUMAN; INTERNET; LOC387715 GENE; NONHUMAN; PHOTORECEPTOR; PIGMENT EPITHELIUM; PLECKSTRIN HOMOLOGY DOMAIN CONTAINING PROTEIN, FAMILY A, MEMBER 1 GENE; PREVALENCE; PRIORITY JOURNAL; RETINA AND ANTERIOR NEURAL FOLD HOMEOBOX LIKE 1 GENE; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; RISK FACTOR;

ANIMALS; COMPLEMENT FACTOR H; DATABASES, FACTUAL; DNA, MITOCHONDRIAL; HUMANS; IMMUNITY, INNATE; MACULAR DEGENERATION; RISK FACTORS;

EID: 79954453398     PISSN: 14346621     EISSN: 14374331     Source Type: Journal    
DOI: 10.1515/CCLM.2011.091     Document Type: Review

References (173)

1. De Jong PT. Age-related macular degeneration. N Engl J Med 2006;355:1474-85. (Pubitemid 44511562)
2. Gorin MB. A new vision for age-related macular degeneration. Eur J Hum Genet 2005;13:793-4. (Pubitemid 40946074)
3. Stone EM, Sheffield VC, Hageman GS. Molecular genetics of age-related macular degeneration. Hum Mol Genet 2001; 10:2285-92. (Pubitemid 32998843)
4. Gorin MB, Breitner JC, De Jong PT, Hageman GS, Klaver CC, Kuehn MH, et al. The genetics of age-related macular degen-eration. Mol Vis 1999;5:29.
5. Klein R. Overview of progress in the epidemiology of age-related macular degeneration. Ophthalmic Epidemiol 2007;14: 184-7. (Pubitemid 47493722)
6. Jager RD, Mieler WF, Miller JW. Age-related macular degen-eration. N Engl J Med 2008;358:2606-17.
7. Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration-emerging pathogenetic and ther-apeutic concepts. Ann Med 2006;38:450-71. (Pubitemid 44767496)
8. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that con-siders 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;20:705-32. (Pubitemid 32918285)
9. Anderson DH, Mullins RF, Hageman GS, Johnson LV A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411-31.
10. Coats G. The structure of the membrane of Bruch, and its rela-tion to the formation of colloid excrescences. Royal London Ophthal Hospital Rep. XVI part II, 1905, pp. 164-178.
11. Hogan M, Alvarado J, Weddell J. Histology of the human eye. Philadelphia: Saunders Company, 1971.
12. Killingsworth MC. Age-related components of Bruch's membrane in the human eye. Graefes Arch Clin Exp Ophthalmol 1987;225:406-12. (Pubitemid 17153712)
13. Marshall J, Hussain AA, Starita C, Moore DJ, Patmore AL. Aging and Bruch's membrane. In: Marmor MF, Wolfensberger TJ, editors. The retinal pigment epithelium. New York: Oxford University Press, 1998:669-92.
14. Guymer R, Bird A. Bruch's membrane, drusen, and age-related macular degeneration. In: Marmor M, Wolfensberger T, editors. The Retinal Pigment Epithelium. New York: Oxford University Press, 1988:693-705.
15. Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988;2:552-77. (Pubitemid 19142671)
16. Chong NH, Keonin J, Luthert PJ, Frennesson CI, Weingeist DM, Wolf RL, et al. Decreased thickness and integrity of the macular elastic layer of Bruch's membrane correspond to the distribution of lesions associated with age-related macular degeneration. Am J Pathol 2005;166:241-51. (Pubitemid 40051676)
17. Ryan SJ. Subretinal neovascularization. Natural history of an experimental model. Arch Ophthalmol 1982;100:1804-9. (Pubitemid 12006673)
18. Malthieu D, Turut P, Francois P. Subretinal neovessels caused by photocoagulation. Bull Soc Ophtalmol Fr 1988;88:645-6.
19. Shen WY, Lee SY, Yeo I, Lai CM, Mathur R, Tan D, et al. Predilection of the macular region to high incidence of choroi-dal neovascularization after intense laser photocoagulation in the monkey Arch Ophthalmol 2004;122:353-60. (Pubitemid 38314197)
20. Pauleikhoff D, Barondes MJ, Minassian D, Chisholm IH, Bird AC Drusen as risk factors in age-related macular disease. Am J Ophthalmol 1990;109:38-43. (Pubitemid 20026486)
21. Abdelsalam A, Del Priore L, Zarbin MA. Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced regression. Surv Ophthalmol 1999; 44:1-29. (Pubitemid 29378350)
22. Bressler NM, Bressler SB, Seddon JM, Gragoudas ES, Jacob-son LP. Drusen characteristics in patients with exudative versus non-exudative age-related macular degeneration. Retina 1988; 8:109-14.
23. Sarks S. Drusen and their relationship to senile macular degen-eration. Aust J Ophthalmol 1980;8:117-30. (Pubitemid 10014380)
24. Lewis H, Straatsma BR, Foos RY Chorioretinal juncture. Mul-tiple extramacular drusen. Ophthalmology 1986;93:1098-112. (Pubitemid 16012722)
25. Frennesson C, Nilsson UL, Nilsson SE. Colour contrast sensi-tivity in patients with soft drusen, an early stage of ARM. Doc Ophthalmol 1995;90:377-86.
26. Holz FG, Gross-Jendroska M, Eckstein A, Hogg CR, Arden GB, Bird AC Colour contrast sensitivity in patients with age-related Bruch's membrane changes. Ger J Ophthalmol 1995;4: 336-41.
27. Midena E, Degli Angeli C, Blarzino MC, Valenti M, Segato T Macular function impairment in eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 1997;38: 469-77. (Pubitemid 27085704)
28. Midena E, Segato T, Blarzino MC, Degli Angeli C Macular drusen and the sensitivity of the central visual field. Doc Ophthalmol 1994;88:179-85.
29. Stangos N, Voutas S, Topouzis F, Karampatakis V Contrast sensitivity evaluation in eyes predisposed to age-related mac-ular degeneration and presenting normal visual acuity Ophthalmologica 1995;209:194-8.
30. Tolentino MJ, Miller S, Gaudio AR, Sandberg MA. Visual field deficits in early age-related macular degeneration. Vision Res 1994;34:409-13. (Pubitemid 24031161)
31. Frennesson C, Nilsson SE. Prophylactic laser treatment in early age-related maculopathy reduced the incidence of exudative complications. Br J Ophthalmol 1998;82:1169-74. (Pubitemid 28474874)
32. Ho AC, Maguire MG, Yoken J, Lee MS, Shin DS, Javornik NB, et al. Laser-induced drusen reduction improves visual func-tion at 1 year. Choroidal Neovascularization Prevention Trial Research Group. Ophthalmology 1999;106:1367-73.
33. Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, 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;39:367-74.
34. Bressler NM, Silva JC, Bressler SB, Fine SL, Green WR. Clinicopathologic correlation of drusen and retinal pigment epi-thelial abnormalities in age-related macular degeneration. Retina 1994;14:130-42. (Pubitemid 24195742)
35. Bressler NM, Bressler SB, Fine SL. Age-related macular degen-eration. Surv Ophthalmol 1988;32:375-413.
36. Bressler NM, Bressler SB, West SK, Fine SL, Taylor HR. The grading and prevalence of macular degeneration in Chesapeake Bay watermen. Arch Ophthalmol 1989;107:847-52. (Pubitemid 19166357)
37. Curcio CA, Medeiros NE, Millican CL. The Alabama age-relat-ed macular degeneration grading system for donor eyes. Invest Ophthalmol Vis Sci 1998;39:1085-96. (Pubitemid 28247342)
38. Green WR. Histopathology of age-related macular degeneration. Mol Vis 1999;5:27.
39. Green WR, Enger C. Age-related macular degeneration histo-pathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993;100:1519-35.
40. Holz FG, Wolfensberger TJ, Piguet B, Gross-Jendroska M, Wells JA, Minassian DC, et al. Bilateral macular drusen in age-related macular degeneration. Prognosis and risk factors. Ophthalmology 1994;101:1522-8. (Pubitemid 24347050)
41. Spraul CW, Grossniklaus HE. Characteristics of Drusen and Bruch's membrane in postmortem eyes with age-related mac-ular degeneration. Arch Ophthalmol 1997;115:267-73. (Pubitemid 27083801)
42. Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L. The Wisconsin age-related maculopathy grading system. Ophthalmology 1991;98:1128-34.
43. Sarks JP, Sarks SH, Killingsworth MC. Evolution of soft drusen in age-related macular degeneration. Eye 1994;8:269-83. (Pubitemid 24229711)
44. Marshall GE, Konstas AG, Reid GG, Edwards JG, Lee WR. Collagens in the aged human macula. Graefes Arch Clin Exp Ophthalmol 1994;232:133-40. (Pubitemid 24091731)
45. Naumann G, Yanoff M, Zimmerman LE. Histogenesis of malig-nant melanomas of the uvea. I. Histopathologic characteristics of nevi of the choroid and ciliary body Arch Ophthalmol 1966;76:784-96.
46. Fishman GA, Apple DJ, Goldberg MF. Retinal and pigment epithelial alterations over choroidal malignant melanomas. Ann Ophthalmol 1975;7:487-9, 491-2.
47. Deutsch TA, Jampol LM. Large druse-like lesions on the sur-face of choroidal nevi. Ophthalmology 1985;92:73-6. (Pubitemid 15170416)
48. D'Souza Y, Duvall-Young J, Mcleod D, Short C, Roberts I, Bonshek R. Ten year review of drusen like lesions in mesan-giocapillary glomerulonephritis II. Invest Ophthalmol Vis Sci 2000;41(Suppl):S164.
49. Duvall-Young J, MacDonald MK, McKechnie NM. Fundus changes in (type II) mesangiocapillary glomerulonephritis sim-ulating drusen: a histopathological report. Br J Ophthalmol 1989;73:297-302. (Pubitemid 19117557)
50. Duvall-Young J, Short CD, Raines MF, Gokal R, Lawler W Fundus changes in mesangiocapillary glomerulonephritis type II: clinical and fluorescein angiographic findings. Br J Ophthalmol 1989;73:900-6. (Pubitemid 20004004)
51. Leys A, Vanrenterghem Y, Van Damme B, Snyers B, Pirson Y Leys M. Fundus changes in membranoproliferative glomeru-lonephritis type II. A fluorescein angiographic study of 23 patients. Graefes Arch Clin Exp Ophthalmol 1991;229: 406-10.
52. Mullins RF, Aptsiauri N, Hageman GS. Structure and compo-sition of drusen associated with glomerulonephritis: implica-tions for the role of complement activation in drusen biogenesis. Eye 2001;15:390-5. (Pubitemid 32600863)
53. Evans K, Gregory CY, Wijesuriya SD, Kermani S, Jay MR, Plant C, et al. Assessment of the phenotypic range seen in Doyne honeycomb retinal dystrophy Arch Ophthalmol 1997; 115:904-10. (Pubitemid 27299165)
54. Piguet B, Haimovici R, Bird AC Dominantly inherited drusen represent more than one disorder: a historical review. Eye 1995;9:34-41.
55. Polkinghorne PJ, Capon MR, Berninger T, Lyness AL, Sehmi K, Bird AC Sorsby's fundus dystrophy. A clinical study Ophthalmology 1989;96:1763-8. (Pubitemid 20013634)
56. Anderson DH, Hageman GS, Mullins RF, Neitz M, Neitz J, Ozaki S, et al. Vitronectin gene expression in the adult human retina. Invest Ophthalmol Vis Sci 1999;40:3305-15.
57. Hageman GS, Mullins RF, Russell SR, Johnson LV, Anderson DH. Vitronectin is a constituent of ocular drusen and the vitro-nectin gene is expressed in human retinal pigmented epithelial cells. FASEB J 1999;13:477-84. (Pubitemid 29115565)
58. Anderson DH, Ozaki S, Nealon M, Neitz J, Mullins RF, Hage-man GS, et al. Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation. Am J Ophthalmol 2001; 131:767-81. (Pubitemid 32522648)
59. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000;14:835-46. (Pubitemid 30241660)
60. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421. (Pubitemid 30349107)
61. Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell 2001;104:503-16.
62. Parums DV, Brown DL, Mitchinson MJ. Serum antibodies to oxidized low-density lipoprotein and ceroid in chronic periaor-titis. Arch Pathol Lab Med 1990;114:383-7. (Pubitemid 20135843)
63. Ross R. Atherosclerosis is an inflammatory disease. Am Heart J 1999;138:S419-20. (Pubitemid 29523224)
64. Bok D. Evidence for an inflammatory process in age-related macular degeneration gains new support. Proc Natl Acad Sci USA 2005;102:7053-4. (Pubitemid 40696331)
65. Shen Y, Meri S. Yin and Yang: complement activation and regulation in Alzheimer's disease. Prog Neurobiol 2003;70: 463-72. (Pubitemid 37249427)
66. Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol 2007;25:1265-75. (Pubitemid 350089828)
67. Gehrs KM, Jackson JR, Brown EN, Allikmets R, Hageman GS. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol 2010;128:349-58.
68. Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A, Gebhard F, et al. Interaction between the coagulation and complement system. Adv Exp Med Biol 2008;632:71-9.
69. Ripoche J, Day AJ, Harris TJ, Sim RB. The complete amino acid sequence of human complement factor H. Biochem J 1988;249:593-602. (Pubitemid 18030952)
70. Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, Murphy BF, et al. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are asso-ciated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet 2006;43:582-9. (Pubitemid 44048765)
71. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, 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 USA 2005;102:7227-32. (Pubitemid 40696361)
72. Kavanagh D, Goodship TH, Richards A. Atypical haemolytic uraemic syndrome. Br Med Bull 2006;77-78:5-22. (Pubitemid 46092270)
73. Rodríguez de Córdoba S, Díaz-Guillén MA, Heine-Suñer D. An integrated map of the human regulator of complement acti-vation (RCA) gene cluster on 1q32. Mol Immunol. 1999; 36: 803-8. (Pubitemid 30100831)
74. McRae JL, Murphy BE, Eyre HJ, Sutherland GR, Crawford J, Cowan PJ. Location and structure of the human FHR-5 gene. Genetica 2002;114:157-61. (Pubitemid 34519770)
75. Soares DC, Gerloff DL, Syme NR, Coulson AF, Parkinson J, Barlow PN. Large-scale modelling as a route to multiple sur-face comparisons of the CCP module family. Protein Eng Des Sel 2005;18:379-88. (Pubitemid 41187254)
76. Walport MJ. Complement. First of two parts. N Engl J Med 2001;344:1058-66.
77. Walport MJ. Complement. Second of two parts. N Engl J Med 2001;344:1140-4.
78. Meri S, Pangburn MK. Discrimination between activators and non-activators of the alternative pathway of complement: reg-ulation via a sialic acid/polyanion binding site on factor H. Proc Natl Acad Sci USA 1990;87:3982-6.
79. Pangburn MK, Pangburn KL, Koistinen V, Meri S, Sharma AK. Molecular mechanisms of target recognition in an innate immune system: interactions among factor H, C3b, and target in the alternative pathway of human complement. J Immunol 2000;164:4742-51. (Pubitemid 30238075)
80. Hocking HG, Herbert AP, Kavanagh D, Soares DC, Ferreira VP, Pangburn MK, et al. Structure of the N-terminal region of complement factor H and conformational implications of dis-ease-linked sequence variations. J Biol Chem 2008;283: 9475-87.
81. Schmidt CQ, Herbert AP, Hocking HG, Uhrín D, Barlow PN. Translational mini-review series on complement factor H: struc-tural and functional correlations for factor H. Clin Exp Immunol 2008;151:14-24. (Pubitemid 350231000)
82. De Córdoba SR, De Jorge EG Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin Exp Immunol 2008;151: 1-13. (Pubitemid 350230999)
83. Holers VM. The spectrum of complement alternative pathway-mediated diseases. Immunol Rev 2008;223:300-16. (Pubitemid 351986186)
84. Walker PD. Dense deposit disease: new insights. Curr Opin Nephrol Hypertens 2007;16:204-12. (Pubitemid 46613706)
85. Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol 2008;143:336-48.
86. Kavanagh D, Richards A, Fremeaux-Bacchi V, Noris M, Goodship T, Remuzzi G, et al. Screening for complement sys-tem abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2007;2:591-6.
87. Donoso LA, Vrabec T, Kuivaniemi H. The role of complement factor H in age-related macular degeneration: a review Surv Ophthalmol 2010;55:227-46.
88. Sun H, Molday RS, Nathans J. Retinal stimulates ATP hydrol-ysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J Biol Chem 1999;274:8269-81.
89. Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, et al. ABCA4 disease progression and a pro-posed strategy for gene therapy Hum Mol Genet 2009;18: 931-41.
90. Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, et al. A photoreceptor cell-specific ATP-bind-ing transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy Nat Genet 1997;15:236-46. (Pubitemid 27098715)
91. Sun H, Nathans J. Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments. Nat Genet 1997;17: 15-6.
92. Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Ven-ning MC, et al. Factor H mutations in hemolytic uremic syn-drome cluster in exons 18-20, a domain important for host cell recognition. Am J Hum Genet 2001;68:485-90. (Pubitemid 32147817)
93. Díaz-Guillén MA, Rodríguez de Córdoba S, Heine-Suñer D. A radiation hybrid map of complement factor H and factor H-related genes. Immunogenetics 1999; 49: 549-52. (Pubitemid 29221789)
94. Józsi M, Richter H, Löschmann I, Skerka C, Buck F, Beisiegel U, et al. FHR-4A: a new factor H-related protein is encoded by the human FHR-4 gene. Eur J Hum Genet 2005;13:321-9. (Pubitemid 40360787)
95. Rodriguez de Cordoba S, Lublin DM, Rubinstein P, Atkinson JP. Human genes for three complement components that reg-ulate the activation of C3 are tightly linked. J Exp Med 1985;161:1189-95. (Pubitemid 15011333)
96. Rodriguez de Cordoba S, Rubinstein P. New alleles of C4-binding protein and factor H and further linkage data in the regulator of complement activation (RCA) gene cluster in man. Immunogenetics 1987;25:267-8. (Pubitemid 17045506)
97. Estaller C, Schwaeble W, Dierich M, Weiss EH. Human com-plement factor H: two factor H proteins are derived from alter-natively spliced transcripts. Eur J Immunol 1991;21:799-802.
98. Schwaeble W, Schwaiger H, Brooimans RA, Barbieri A, Möst J, Hirsch-Kauffmann M, et al. Human complement factor H. Tissue specificity in the expression of three different mRNA species. Eur J Biochem 1991;198:399-404.
99. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421-4. (Pubitemid 40530082)
100. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308: 419-21. (Pubitemid 40530081)
101. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-9. (Pubitemid 40530070)
102. Okamoto H, Umeda S, Obazawa M, Minami M, Noda T Mizota A, et al. Complement factor H polymorphisms in Jap-anese population with age-related macular degeneration. Mol Vis 2006;12:156-8. (Pubitemid 43329568)
103. Li M, Atmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS, et al. CFH haplotypes without the Y402H cod-ing variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 2006;38:1049-54. (Pubitemid 44325931)
104. Hageman GS, Hancox LS, Taiber AJ, Gehrs KM, Anderson DH, Johnson LV, et al. Extended haplotypes in the comple-ment factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: char-acterization, ethnic distribution and evolutionary implications. Ann Med 2006;38:592-604. (Pubitemid 46292019)
105. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T Chakravarthy U. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 2006;38:1173-7. (Pubitemid 44470363)
106. Boon CJ, Klevering BJ, Hoyng CB, Zonneveld-Vrieling MN, Nabuurs SB, Blokland E, et al. Basal laminar drusen caused by compound heterozygous variants in the CFH gene. Am J Hum Genet 2008;82:516-23. (Pubitemid 351726101)
107. Bergeron-Sawitzke J, Gold B, Olsh A, Schlotterbeck S, Lem-on K, Visvanathan K, et al. Multilocus analysis of age-related macular degeneration. Eur J Hum Genet 2009;17:1190-9.
108. Klein ML, Schultz DW, Edwards A, Matise TC, Rust K, Ber-selli CB, et al. Age-related macular degeneration. Clinical fea-tures in a large family and linkage to chromosome 1q. Arch Ophthalmol 1998;116:1082-8. (Pubitemid 29101833)
109. Schultz DW, Weleber RG, Lawrence G, Barral S, Majewski J, Acott TS, et al. HEMICENTIN-1 (FIBULIN-6) and the 1q31 AMD locus in the context of complex disease: review and perspective. Ophthalmic Genet 2005;26:101-5. (Pubitemid 41780292)
110. Combadière C, Feumi C, Raoul W, Keller N, Rodéro M, Pézard A, et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-relat-ed macular degeneration. J Clin Invest 2007;117:2920-8. (Pubitemid 47529622)
111. Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 2009;17:100-4.
112. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibil-ity to age-related macular degeneration. Proc Natl Acad Sci USA 2010;107:7401-6.
113. Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 1998;95:588-93. (Pubitemid 28083787)
114. Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D, et al. Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 2008;359: 1456-63.
115. Edwards AO, Swaroop A, Seddon JM. Geographic atrophy in age-related macular degeneration and TLR3. N Engl J Med 2009;360:2254-5; author reply 2255-6.
116. Allikmets R, Bergen AA, Dean M, Guymer RH, Hageman GS, Klaver CC, et al. Geographic atrophy in age-related mac-ular degeneration and TLR3. N Engl J Med 2009;360:2252-4; author reply 2255-6.
117. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, et al. Variation in factor B (BF) and complement compo-nent 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006;38:458-62.
118. Christie DL, Gagnon J. Amino acid sequence of the Bb frag-ment from complement factor B. Sequence of the major cyan-ogen bromide-cleavage peptide (CB-II) and completion of the sequence of the Bb fragment Biochem J 1983;209:61-70. (Pubitemid 13153637)
119. Lokki ML, Koskimies SA. Allelic differences in hemolytic activity and protein concentration of BF molecules are found in association with particular HLA haplotypes. Immunoge-netics 1991;34:242-6.
120. Boekhoorn SS, Vingerling JR, Uitterlinden AG, Van Meurs JB, van Duijn CM, Pols HA, et al. Estrogen receptor alpha gene polymorphisms associated with incident aging macula disorder. Invest Ophthalmol Vis Sci 2007;48:1012-7. (Pubitemid 351261391)
121. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-76. (Pubitemid 36749215)
122. Churchill AJ, Carter JG, Lovell HC, Ramsden C, Turner SJ, Yeung A, et al. VEGF polymorphisms are associated with neovascular age-related macular degeneration. Hum Mol Genet 2006;15:2955-61. (Pubitemid 44446814)
123. Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agar-wal A, Postel EA, et al. Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci 2006;47:329-35. (Pubitemid 46780832)
124. Lin JM, Wan L, Tsai YY, Lin HJ, Tsai Y, Lee CC, et al. Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration. Am J Ophthalmol 2008; 145:1045-51.
125. Richardson AJ, Islam FM, Guymer RH, Cain M, Baird PN. A tag-single nucleotide polymorphisms approach to the vas-cular endothelial growth factor-A gene in age-related macular degeneration. Mol Vis 2007;13:2148-52. (Pubitemid 350200387)
126. De Jong PT, Bockhoorn SS, Vingerling JR, Uitterlinden AG, Hoffman A. Polymorphisms in the vascular endothelial growth factor gene and risk of aging macula disorder: the Rotterdam study Invest Ophthalmol Vis Sci 2007;48:E-2119.
127. Smith SR, Tong Z, Constantine R, Brinton E, Cameron J, Gibbs D, et al. Vascular endothelial growth factor (VEGF) polymorphisms and their association with age-related macular degeneration. Invest Ophthalmol Vis Sci 2007;48:E-2097.
128. Zareparsi S, Buraczynska M, Branham KE, Shah S, Eng D, Li M, et al. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet 2005;14:1449-55. (Pubitemid 40834203)
129. Edwards AO, Chen D, Fridley BL, James KM, Wu Y, Abe-casis G, et al. Toll-like receptor polymorphisms and age-relat-ed macular degeneration. Invest Ophthalmol Vis Sci 2008; 49:1652-9.
130. Troelstra C, van Gool A, de Wit J, Vermeulen W, Bootsma D, Hoeijmakers JH. ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes. Cell 1992;71:939-53.
131. Tuo J, Ning B, Bojanowski CM, Lin ZN, Ross RJ, Reed GF et al. Synergic effect of polymorphisms in ERCC6 5' flanking region and complement factor H on age-related macular degeneration predisposition. Proc Natl Acad Sci USA 2006;103:9256-61. (Pubitemid 43902565)
132. Zumbrunn J, Trueb B. Primary structure of a putative serine protease specific for IGF-binding proteins. FEBS Lett 1996;398:187-92. (Pubitemid 26414307)
133. Zumbrunn J, Trueb B. Localization of the gene for a serine protease with IGF-binding domain (PRSS11) to human chro-mosome 10q25.3-q26.2. Genomics 1997;45:461-2. (Pubitemid 27467648)
134. Chien J, Staub J, Hu SI, Erickson-Johnson MR, Couch FJ, Smith DI, et al. A candidate tumor suppressor HtrA1 is down-regulated in ovarian cancer. Oncogene 2004;23:1636-44. (Pubitemid 38406528)
135. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, et al. HTRA1 promoter polymorphism in wet age-related mac-ular degeneration. Science 2006;314:989-92. (Pubitemid 44749943)
136. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992-3. (Pubitemid 44749944)
137. Mori K, Horie-Inoue K, Kohda M, Kawasaki I, Gehlbach PL, Awata T, et al. Association of the HTRA1 gene variant with age-related macular degeneration in the Japanese population. J Hum Genet 2007;52:636-41. (Pubitemid 47012535)
138. Wang QL, Chen S, Esumi N, Swain PK, Haines HS, Peng G, et al. QRX, a novel homeobox gene, modulates photoreceptor gene expression. Hum Mol Genet 2004;13:1025-40. (Pubitemid 38702189)
139. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA 2007;104:16227-32. (Pubitemid 350099389)
140. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, et al. Age-related macular degeneration is asso-ciated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 2008;40:892-6. (Pubitemid 351913654)
141. Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, con-tributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14:3227-36. (Pubitemid 41631297)
142. 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. (Pubitemid 41192646)
143. Weeks DE, Conley YP, Tsai HJ, Mah TS, Schmidt S, Postel EA, 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;75:174-89. (Pubitemid 38943862)
144. Conley YP, Jakobsdottir J, Mah T, Weeks DE, Klein R, Kuller L, et al. CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet 2006; 15:3206-18. (Pubitemid 44605500)
145. Mullins RF, Olvera MA, Clark AF, Stone EM. Fibulin-5 dis-tribution in human eyes: relevance to age-related macular degeneration. Exp Eye Res 2007;84:378-80. (Pubitemid 44958467)
146. Hasham SN, Pillarisetti S. Vascular lipases, inflammation and atherosclerosis. Clin Chim Acta 2006;372:179-83. (Pubitemid 44286780)
147. Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, 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 USA 2010;107:7395-400.
148. Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998;63:200-6. (Pubitemid 30428336)
149. Schultz DW, Klein ML, Humpert A, Majewski J, Schain M, Weleber RG, et al. Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch Ophthalmol 2003;121:679-83. (Pubitemid 36554471)
150. Baird PN, Richardson AJ, Robman LD, Dimitrov PN, Tikellis G, McCarty CA, et al. Apolipoprotein (APOE) gene is asso-ciated with progression of age-related macular degeneration (AMD). Hum Mutat 2006;27:337-42.
151. Bojanowski CM, Shen D, Chew EY, Ning B, Csaky KG, Green WR, et al. An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation. Environ Mol Mutagen 2006;47:594-602. (Pubitemid 44701595)
152. 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;39:1200-1. (Pubitemid 47482689)
153. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007;357:553-61. (Pubitemid 47236280)
154. Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, et al. Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family Hum Mol Genet 2003;12:3315-23. (Pubitemid 37541077)
155. Zurdel J, Finckh U, Menzer G, Nitsch RM, Richard G CST3 genotype associated with exudative age related macular degeneration. Br J Ophthalmol 2002;86:214-9. (Pubitemid 34127549)
156. De La Paz MA, Pericak-Vance MA, Lennon F, Haines JL, Seddon JM. Exclusion of TIMP3 as a candidate locus in age-related macular degeneration. Invest Ophthalmol Vis Sci 1997;38:1060-5. (Pubitemid 27227035)
157. Felbor U, Doepner D, Schneider U, Zrenner E, Weber BH. Evaluation of the gene encoding the tissue inhibitor of metal-loproteinases-3 in various maculopathies. Invest Ophthalmol Vis Sci 1997;38:1054-9. (Pubitemid 27227034)
158. Jarrett SG, Lin H, Godley BF, Boulton ME. Mitochondrial DNA damage and its potential role in retinal degeneration. Prog Retin Eye Res 2008;27:596-607.
159. Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C Mitochondrial alterations of retinal pigment epi-thelium in age-related macular degeneration. Neurobiol Aging 2006;27:983-93. (Pubitemid 44262273)
160. Karunadharma PP, Nordgaard CL, Olsen TW, Ferrington DA. Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:5470-9.
161. Canter JA, Olson LM, Spencer K, Schnetz-Boutaud N, Ander-son B, Hauser MA, et al. Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PLoS One 2008;3:e2091.
162. Udar N, Atilano SR, Memarzadeh M, Boyer DS, Chwa M, Lu S, et al. Mitochondrial DNA haplogroups associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:2966-74.
163. SanGiovanni JP, Arking DE, Iyengar SK, Elashoff M, Cle-mons TE, Reed GF, et al. Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS One 2009;4:e5508.
164. Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, et al. The Framingham Eye Study mono-graph: an ophthalmological and epidemiological study of cat-aract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of2631 adults, 1973-1975. Surv Ophthalmol 1980;24(Suppl):335-610.
165. Marshall J. The ageing retina: physiology or pathology Eye 1987;1:282-95. (Pubitemid 17126432)
166. Young RW. Pathophysiology of age-related macular degen-eration. Surv Ophthalmol 1987;31:291-306.
167. 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;126:115-21.
168. Klein R, Klein BE, Tomany SC, Moss SE. Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye study Am J Epidemiol 2002;156:589-98.
169. Tan JS, Mitchell P, Kifley A, Flood V Smith W, Wang JJ. Smoking and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye study Arch Ophthalmol 2007;125:1089-95. (Pubitemid 47258039)
170. Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH. Alcohol consumption and the risk of age-related macular degeneration: a systematic review and meta-analysis. Am J Ophthalmol 2008;145:707-15.
171. Chong EW, Kreis EJ, Wong TY, Simpson AJ, Guymer RH. Dietary antioxidants and primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Br Med J 2007;335:755.
172. Klein BE, Klein R, Lee KE, Jensen SC. Measures of obesity and age-related eye diseases. Ophthalmic Epidemiol 2001;8: 251-62. (Pubitemid 32681945)
173. Hirvela H, Luukinen H, Laara E, Sc L, Laatikainen L. Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology 1996;103:871-7. (Pubitemid 26190719)