Survey of Ophthalmology
Volume 55, Issue 3 , Pages 227-246 , May 2010

The Role of Complement Factor H in Age-related Macular Degeneration: A Review

  • Larry A. Donoso, MD, PhD

      Affiliations

    • The Philadelphia Retina Endowment Fund, The Eye Research Institute, and the Wills Eye Institute, Philadelphia, Pennsylvania, USA
    • Corresponding Author InformationReprint address: Larry A. Donoso, MD, PhD, PO Box 53429, Philadelphia, PA 19105.
  • ,
  • Tamara Vrabec, MD

      Affiliations

    • The Geisinger Medical Center, Danville, Pennsylvania, USA
  • ,
  • Helena Kuivaniemi, MD, PhD

      Affiliations

    • The Geisinger Medical Center, Danville, Pennsylvania, USA

References 

  1. Abrera-Abeleda MA, Nishimura C, Smith JL, et al. Variations in the complement regulatory genes factor H (cfh) and factor H related 5 (cfhr5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet. 2006;43:582–589
  2. Adeyemo A, Rotimi C. Genetic variations associated with complex human diseases show wide cariation across multiple populations. Public Health Genomics. 2010;13(2):72–79
  3. Altshuler D, Daly MJ, Landers ES. Genetic mapping in human disease. Science. 2008;322(5903):881–888
  4. An F, Li Q, Tu Z, et al. Daf protects against T cell autoreactivity that leads to experiment autoimmune uveitis. Invest Ophthalmol Vis Sci. 2009;50(8):3778–3782
  5. Anderson DH, Mullins RF, Hageman GS, et al. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134(3):411–431
  6. Anderson DH, Ozaki S, Nealon M, 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(6):767–781
  7. Anderson DH, Talaga KC, Rivest AJ, et al. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res. 2004;78(2):243–256
  8. Anderson DR, Tsutsui JM, Xie F, et al. The role of complement in the adherence of microbubbles to dysfunctional arterial endothelium and atherosclerotic plaque. Cardiovasc Res. 2007;73(3):597–606
  9. Appel GB, Cook HT, Hageman G, et al. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol. 2005;16(5):1392–1403
  10. Appel GB. Immun-complex glomerulonephritis-deposits plus interest. N Eng J Med. 1993;328(7):466–470
  11. Ashwell G, Morell AG. The role of surface carbohydrates in the hepatic recognition and transport of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol. 1974;41:99–128
  12. Badger SA, Soong CV, O'Donnell ME, et al. C-reactive protein (CRP) elevation in patients with abdominal aortic aneurysm is independent of the most important CRP genetic polymorphism. J Vasc Surg. 2009;49(1):178–184
  13. Barlow PN, Hageman GS, Lea SM. Complement factor H: using atomic resolution structure to illuminate disease mechanisms. Adv Exp Med Biol. 2008;632:117–142
  14. Barreto C, Heintz J, Horner J, et al. Original biomaterials preserved in dinosaur bone. Microsc Microcanal. 2007;13:52–54
  15. Beutel J, Rudolf M, Grisanti S. Current and future therapies for age-related macular degeneration. Expert Opin Emerg Drugs. 2009;14(2):341–362
  16. Boddy AM, Lenk GM, Lillus JHN, et al. Basic research studies to understand aneurysmal disease. Drug News Perspective. 2008;21:142
  17. Brantley MA, Edelstein SL, King JM, et al. Association of complement factor H and loc387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy. Eye. 2009;23:626–631
  18. Brantley MA, Edelstein SL, King JM, et al. Clinical phenotypes associated with the complement factor H y402h variant in age-related macular degeneration. Am J Ophthalmol. 2007;144:404–408
  19. Brantley MA, Fang AM, King JM, et al. Association of complement factor H and loc387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology. 2007;114:2168–2173
  20. Capella JF, Paik DC, Yin NX, et al. Complement activation and subclassification of tissue immunoglobulin G in the abdominal aortic aneurysm. J Surg Res. 1996;65(1):31–33
  21. Caprioli J, Bettinaglio P, Zipfel PF, et al. The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol. 2001;12(2):297–307
  22. Clark SJ, Higman VA, Mulloy B, et al. His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form. J Biol Chem. 2006;281(34):24713–24720
  23. Corbett BA. A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. Mol Psychiatry. 2007;12:292–306
  24. De Cardoba SR. The human complement factor H: functional roles, genetic variations, and disease associations. Mol Immunol. 2004;41:355–367
  25. 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):1–13
  26. Despriet DD, Klaver CC, Witteman JC, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006;296(3):301–309
  27. Dizikes GJ. Update on the human genome project. Clin Lab Med. 1995;15(4):973–988
  28. Donoso LA, Kim D, Frost A, et al. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2006;51(2):137–152
  29. Donoso LA, Merryman CF, Edelberg KE, et al. S-antigen in the developing retina and pineal gland: a monoclonal antibody study. Invest Ophthalmol Vis Sci. 1985;26(4):561–567
  30. Donoso LA, Nagy RM, McFall RC, et al. Metastatic choroidal melanoma: hepatic binding protein reactivity towards a live metastasinzing clone. Arch Ophthalmol. 1983;101:787–790
  31. Donoso LA, Roake LB, Shieks JA, et al. S-antigen immunoreactivity in trilateral retinoblastoma. Am J Ophthalmol. 1987;103:357–362
  32. D'souza YB, Jones CJ, Short CD, et al. Oligosaccharide composition is similar in drusen and dense deposits in membranoproliferative glomerulonephritis type II. Kidney Int. 2009;75(8):824–827
  33. Edwards AO, Ritter R, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–424
  34. Engel LW. The human genome project. History, goals, and progress to date. Arch Pathol Lab Med. 1993;117:459–465
  35. Ferrara DC, Merriam JE, Freund KB, et al. Analysis of major alleles associated with age-related macular degeneration in patients with multifocal choroiditis: strong association with complement factor H. Arch Ophthalmol. 2008;126(11):1562–1566
  36. Francis PJ, Schultz DW, Hamon S, et al. Haplotypes in the complement factor H (CFH) gene: associations with drusen and advanced age-related macular degeneration. PLoS One. 2007;2(11):e1197
  37. 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):458–462
  38. Gotoh N, Yamada R, Nakanishii H. Correlation between cfh y402h and htra rs11200638 genotype to typical exudative age-related macular degeneration and polypoidal choroidal vasculopaty phenotype in the japanese population. Clin Exp Ophthalmol. 2008;36:437–442
  39. Grassi MA, Fingert JH, Scheetz TE, et al. Ethnic variation in AMD-associated complement factor H polymorphism. tyr402his. Hum Mutat. 2006;27:921–925
  40. Grassi MA, Folk JC, Scheetz TE, et al. Complement factor H polymorphism p.tyr402his and cuticular drusen. Arch Ophthalmol. 2007;125:93–97
  41. Grewal PK, Uchiyama S, Ditto D, et al. The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med. 2008;14:648–655
  42. Group ISMW. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature. 2001;409:928–932
  43. Guyer MS, Collins FS. The Human Genome Project and the future of medicine. Am J Dis Child. 1993;147(11):1145–1152
  44. Haapasalo K, Jarva H, Siljander T, et al. Complement factor H allotype 402h is associated with increased c3b opsonization and phagocytosis of streptococcus pyogenes. Mol Microbiol. 2008;70(3):583–594
  45. Haas P, Steindl K, Schmid-Kubista KE, et al. Complement factor H gene polymorphisms and chlamydia pneumoniae infection in age-related macular degeneration. Eye. 2009;23:2228–2232
  46. Haddad S, Chen CA, Santangelo SL, et al. The genetics of age-related macular degeneration: a review of progress to date. Surv Ophthalmol. 2006;51(4):316–363
  47. 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 USA. 2005;102(20):7227–7232
  48. Hageman GS, Hancox LS, Taiber AJ, et al. Extended haplotypes in the complement factor H (cfh) and cfh-related (cfhr) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med. 2006;38(8):592–604
  49. 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):705–732
  50. Hageman GS, Mullins RF. Molecular composition of drusen as related to substructural phenotype. Mol Vis. 1999;5:28
  51. Hageman GS, Mullins RF, Russell SR, et al. Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J. 1999;13(3):477–484
  52. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419–421
  53. Hakobyan S, Harris CL, Tortajada A, et al. Measurement of factor H variants in plasma using variant-specific monoclonal antibodies: application to assessing risk of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49(5):1983–1990
  54. Hamilton G, Proitsi P, Williams J, et al. Complement factor H y402h polymorphism is not associated with late-onset Alzheimer's disease. Neuromolecular Med. 2007;9(4):331–334
  55. Hansson AS, Johannesson M, Svensson L, et al. Relapsing polychondritis, induced in mice with matrilin 1, is an antibody and complement-dependent disease. Am J Pathol. 2004;164:95–966
  56. Heinen S, Jozsi M, Hartmann A, et al. Hemolytic uremic syndrome: a factor H mutation (e1172stop) causes defective complement control at the surface of endothelial cells. J Am Soc Nephrol. 2007;18:506–514
  57. Heinen S, Sanchez-Corral P, Jackson MS, et al. De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mutat. 2006;27(3):292–293
  58. Herbert AP, Deakin JA, Schmidt CQ, et al. Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration–linked single nucleotide polymorphism. J Biol Chem. 2007;282(26):18960–18968
  59. Herbert AP, Uhrin D, Lon M, et al. Disease-associated sequence variations congregate in a polyanion-recognition patch on human factor H revealed in 3d structure. J Biol Chem. 2006;281:16512–16520
  60. Herman JH, Dennis MV. Immunopathologic studies in relapsing polychondritis. J Clin Invest. 1973;52(3):549–558
  61. Herzberger P, Siegel C, Skerka C, et al. Identification and characterization of the factor H and fhl-1 binding complement regulator-acquiring surface protein 1 of the Lyme disease spirochete Borrelia spielmanii sp. nov. Int J Med Microbiol. 2009;299:141–154
  62. Herzberger P, Siegel C, Skerka C, et al. Human pathogenic Borrelia spielmanii sp. nov. resists complement-mediated killing by direct binding of immune regulators factor H and factor h–like protein 1. Infect Immun. 2007;75:4817–4825
  63. Hocking HG, Herbert AP, Kavanagh D, et al. Structure of the n-terminal region of complement factor H and conformational implications of disease-linked sequence variations. J Biol Chem. 2008;283(14):9475–9487
  64. Holers VM. The spectrum of complement alternative pathway–mediated diseases. Immunol Rev. 2008;223:300–316
  65. Hovis KM, McDowell JV, Griffin L, et al. Identification and characterization of a linear-plasmid-encoded factor H–binding protein (fhba) of the relapsing fever spirochete borrelia hermsii. J Bacteriol. 2004;186(9):2612–2618
  66. Hughes AE, Orr N, Esfandiary H, et al. A common cfh haplotype, with deletion of cfhr1 and cfhr3, is associated with lower risk of age-related macular degeneration. Nat Genet. 2006;38(10):1173–1177
  67. Hughes AE, Orr N, Patterson C, et al. Neovascular age-related macular degeneration risk based on cfh, loc387715/htra1. smoking. PLoS Med. 2007;4(12):e355
  68. Hütter G, Nowak D, Mossner M, et al. Long-term control of hiv by ccr5 delta32/delta32 stem-cell transplantation. N Engl J Med. 2009;360(7):692–698
  69. Inward C, et al. Haemolytic uraemic syndrome. Paediatrics and Child Health. 2008;18:364–368
  70. Jallanko J, Peltonen S, Koskinen A, et al. Successful liver–kidney transplantation in two children with aHUS caused by a mutation in complement factor H. Am J Transplant. 2008;8:216–221
  71. Janeway CA. Immunobiology: The Immune System in Health and Disease. ed 6. New York: Garland Science; 2005;
  72. Janssen BJ, Halff EF, Lambris JD, et al. Structure of compstatin in complex with complement component c3c reveals a new mechanism of complement inhibition. J Biol Chem. 2007;282(40):29241–29247
  73. Johnson LV, Leitner WP, Rivest AJ, et al. The Alzheimer's a beta–peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci USA. 2002;99(18):11830–11835
  74. Johnson PT, Betts KE, Radeke MJ, et al. Individuals homozygous for the age-related macular degeneration risk–conferring variant of complement factor H have elevated levels of crp in the choroid. Proc Natl Acad Sci USA. 2006;103(46):17456–17461
  75. Józsi M, Heinen S, Hartmann A, et al. Factor H and atypical hemolytic uremic syndrome: mutations in the c-terminus cause structural changes and defective recognition functions. J Am Soc Nephrol. 2006;17(1):170–177
  76. Józsi M, Licht C, Strobel S, et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with cfhr1/cfhr3 deficiency. Blood. 2008;111(3):1512–1514
  77. Józsi M, Strobel S, Dahse HM, et al. Anti factor H autoantibodies block c-terminal recognition function of factor H in hemolytic uremic syndrome. Blood. 2007;110(5):1516–1518
  78. Józsi M, Zipfel PF. Factor H family proteins and human diseases. Trends Immunol. 2008;29(8):380–387
  79. Jylhava J, Eklund C, Pessi T, et al. Genetics of c-reactive protein and complement factor H have an epistatic effect on carotid artery compliance: the cardiovascular risk in young finns study. Clin Exp Immunol. 2009;155:53–58
  80. Jylhävä J, Eklund C, Jylhä M, et al. Complement factor H 402his variant confers an increased mortality risk in finnish nonagenarians: the vitality 90+ study. Exp Gerontol. 2009;44(4):297–299
  81. Kelly U, Rickman CB, Postel EA, et al. Rapid and sensitive method for detection of y402, h402, i62, and v62 variants of complement factor H in human plasma samples using mass spectrometry. Invest Ophthalmol Vis Sci. 2009;50(4):1540–1545
  82. Kim NR, Kang JH, Kwon OW, et al. Association between complement factor H gene polymorphisms and neovascular age related macular degeneration in Koreans. Invest Ophthalmol Vis Sci. 2008;49:2071–2076
  83. 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):1019–1025
  84. Klein RJ, Zeiss C, Chew EY, et al. Complement Factor H polymorphism in age related macular degeneration. Science. 2009;308:385–389
  85. Kondo N, Honda S, Kuno S, et al. Coding variant i62v in the complement factor H gene is strongly associated with polypoidal choroidal vasculopathy. Ophthalmology. 2009;116(2):304–310
  86. Koziolek MJ, Zipfel PF, Skerka C, et al. Chronic course of a hemolytic uremic syndrome caused by a deficiency of factor h–related proteins (cfhr1 and cfhr3). Kidney Int. 2008;74(3):384–388
  87. Kraiczy P, Hellwage J, Skerka C, et al. Immune evasion of borrelia burgdorferi: mapping of a complement-inhibitor factor h–binding site of bbcrasp-3, a novel member of the ERP protein family. Eur J Immunol. 2003;33(3):697–707
  88. Kuivaniemi H, Platsoucas CD, Tilson MD. Aortic aneurysms: an immune disease with a strong genetic component. Circulation. 2008;117(2):242–252
  89. Laine M, Jarva H, Seitsonen S, et al. Y402h polymorphism of complement factor H affects binding affinity to c-reactive protein. J Immunol. 2007;178(6):3831–3836
  90. Lee AY, Brantley MA. Cfh and loc387715/arms2 genotypes and antioxidants and zinc therapy for age-related macular degeneration. Pharmacogenomics. 2008;9(10):1547–1550
  91. Lee SS, Robinson MR. Novel drug delivery systems for retinal diseases. A review. Ophthalmic Res. 2009;41(3):124–135
  92. Lenk GM, Tromp G, Weinsheimer S, et al. Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms. BMC Genomics. 2007;8:237
  93. Lerner MP, Donoso LA, Nordquist RE, et al. Immunological mimicry between retinal S-antigen and group a streptococcal m proteins. Autoimmunity. 1995;22(2):95–106
  94. 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):1049–1054
  95. Licht C, Heinen S, Józsi M, et al. Deletion of lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int. 2006;70(1):42–50
  96. Magargal LE, Donoso LA, Goldberg RE, et al. Ocular manifestations of relapsing polychondritis. Retina. 1981;1(2):96–99
  97. Mandal MN, Ayyagari R. Complement factor H: spatial and temporal expression and localization in the eye. Invest Ophthalmol Vis Sci. 2006;47(9):4091–4097
  98. Markiewski MM. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 2007;171:715–727
  99. Martinez-Barricarte R, Pianetti G, Gautard R, et al. The complement factor H r1210c mutation is associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2008;19:639–646
  100. McKay GJ, Silvestri G, Patterson CC, et al. Further assessment of the complement component 2 and factor B region associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50(2):533–539
  101. Montes T, Goicoechea de Jorge E, Ramos R, et al. Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis. Mol Immunol. 2008;45(10):2897–2904
  102. Morell AG, Irvine RA, Sternlieb I, et al. Physical and chemical studies on ceruloplasmin. v. metabolic studies on sialic acid–free ceruloplasmin in vivo. J Biol Chem. 1968;243(1):155–159
  103. Mullins RF, Aptsiauri N, Hageman GS. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond). 2001;15(Pt 3):390–395
  104. Mullins RF, Hageman GS. Human ocular drusen possess novel core domains with a distinct carbohydrate composition. J Histochem Cytochem. 1999;47(12):1533–1540
  105. Mullins RF, Johnson LV, Anderson DH, et al. Characterization of drusen-associated glycoconjugates. Ophthalmology. 1997;104(2):288–294
  106. Mullins RF, Russell SR, Anderson DH, et al. 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(7):835–846
  107. Murphy B, Georgiou T, Machet D, et al. Factor H–related protein-5: a novel component of human glomerular immune deposits. Am J Kidney Dis. 2002;39(1):24–27
  108. Närkiö-Mäkelä M, Hellwage J, Tahkokallio O, et al. Complement-regulator factor H and related proteins in otitis media with effusion. Clin Immunol. 2001;100(1):118–126
  109. Noris M, Ruggenenti P, Perna A, et al. Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. J Am Soc Nephrol. 1999;10:281–293
  110. Ormsby RJ, Ranganathan S, Tong JC, et al. Functional and structural implications of the complement factor H y402h polymorphism associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49(5):1763–1770
  111. Pagano MB, Zhou HF, Ennis TL, et al. Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm. Circulation. 2009;119(13):1805–1813
  112. Prosser BE, Johnson S, Roversi P, et al. Expression, purification, cocrystallization and preliminary crystallographic analysis of sucrose octasulfate/human complement regulator factor H scrs 6–8. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007;63(Pt 6):480–483
  113. Qin S, Rodrigues G, et al. Progress and perspectives on the role of rpe cell inflammatory responses in the development of age-related macular degeneration. J Inflamm Res. 2008;1:49–65
  114. Ram S, McQuillen DP, Gulati S, et al. Binding of complement factor H to loop 5 of porin protein 1a: a molecular mechanism of serum resistance of nonsialylated neisseria gonorrhoeae. J Exp Med. 1998;188(4):671–680
  115. Read RW, Szalai AJ, Vogt SD, et al. Genetic deficiency of c3 as well as CNS-targeted expression of the complement inhibitor sCrry ameliorates experimental autoimmune uveoretinitis. Exp Eye Res. 2006;82(3):389–394
  116. Russell SR, Mullins RF, Schneider BL, et al. Location, substructure, and composition of basal laminar drusen compared with drusen associated with aging and age-related macular degeneration. Am J Ophthalmol. 2000;129(2):205–214
  117. Saunders RE, Abarrategui-Garrido C, Frémeaux-Bacchi V, et al. The interactive factor h–atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and factor I mutations with structural models. Hum Mutat. 2007;28(3):222–234
  118. 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):852–864
  119. Schneider MC, Exley RM, Chan H, et al. Functional significance of factor H binding to neisseria meningitidis. J Immunol. 2006;176(12):7566–7575
  120. Schneider MC, Prosser BE, Caesar JJ, et al. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature. 2009;458(7240):890–893
  121. Scholl HP, Weber BH, Nöthen MM, et al. [y402h polymorphism in complement factor H and age-related macula degeneration (AMD)]. Ophthalmologe. 2005;102(11):1029–1035
  122. 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
  123. Seddon JM, Reynolds R, Maller J, et al. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009;50(5):2044–2053
  124. Seddon JM, Reynolds R, Rosner B. Peripheral retinal drusen and reticular pigment: association with cfhy402h and cfhrs1410996 genotypes in family and twin studies. Invest Ophthalmol Vis Sci. 2009;50(2):586–591
  125. Seko Y, Azuma N, Takahashi Y, et al. Human sclera maintains common characteristics with cartilage throughout evolution. PLoS One. 2008;3(11):e3709
  126. Sethi S, Gamez JD, Varna JA, et al. Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int. 2009;75(9):876–879
  127. Shuler RK, Hauser MA, Caldwell J, et al. Neovascular age-related macular degeneration and its association with loc387715 and complement factor H polymorphism. Arch Ophthalmol. 2007;125:63–67
  128. Shuler RK, Schmidt S, Gallins P. Peripheral reticular pigmentary change is associated with complement factor H polymorphism (y402h) in age-related macular degeneration. Ophthalmology. 2008;115:520–524
  129. Singh VK, Usukura J, Shinohara T. Molecular mimicry: uveitis induced in macaca fascicularis by microbial protein having sequence homology with retinal S-antigen. Jpn J Ophthalmol. 1992;36(1):108–116
  130. Singh VK, Yamaki K, Abe T, et al. Molecular mimicry between uveitopathogenic site of retinal S-antigen and Escherichia coli protein: induction of experimental autoimmune uveitis and lymphocyte cross-reaction. Cell Immunol. 1989;122(1):262–273
  131. Skerka C, Józsi M, Zipfel PF, et al. Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost. 2009;101(2):227–232
  132. Skerka C, Lauer N, Weinberger AA, et al. Defective complement control of factor H (y402h) and fhl-1 in age-related macular degeneration. Mol Immunol. 2007;44(13):3398–3406
  133. Smith RJ, Alexander J, Barlow PN, et al. New approaches to the treatment of dense deposit disease. J Am Soc Nephrol. 2007;18(9):2447–2456
  134. Spencer KL, Hauser MA, Olson LM, et al. Deletion of cfhr3 and cfhr1 genes in age-related macular degeneration. Hum Mol Genet. 2008;17(7):971–977
  135. Spencer KL, Hauser MA, Olson LM, et al. Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet. 2007;16(16):1986–1992
  136. Spencer KL, Hauser MA, Olson LM, et al. Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration. Invest Ophthalmol Vis Sci. 2007;48(9):4277–4283
  137. Stella A, Gargiulo M, Pasquinelli G, et al. The cellular component in the parietal infiltrate of inflammatory abdominal aortic aneurysms (IAAA). Eur J Vasc Surg. 1991;5(1):65–70
  138. Thakkinstian A, Han P, McEvoy M, et al. Systematic review and meta-analysis of the association between complement factor H y402h polymorphisms and age-related macular degeneration. Hum Mol Genet. 2006;15(18):2784–2790
  139. Watson JD, Crick FH. A structure for deoxyribose nucleic acid. Nature. 1953;171:737–738
  140. Wegscheider BJ, Weger M, Renner W, et al. Association of complement factor H y402h gene polymorphism with different subtypes of exudative age-related macular degeneration. Ophthalmology. 2007;114(4):738–742
  141. Wildner G, Diedrichs-Möhring M. Autoimmune uveitis induced by molecular mimicry of peptides from rotavirus, bovine casein and retinal S-antigen. Eur J Immunol. 2003;33(9):2577–2587
  142. Xing C, Sivakumaran TA, Wang JJ, et al. Complement factor H polymorphisms, renal phenotypes and age-related macular degeneration: The Blue Mountains Eye Study. Genes Immun. 2008;9(3):231–239
  143. Xu H, Chen M, Forrester JV. Para-inflammation in the ageing retina. Prog Retina Eye Res. 2009;28(5):348–368
  144. Zarbin M, Szirth B. Current treatment of age-related macular degeneration. Optom Vis Sci. 2007;84(7):559–572
  145. 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):149–153
  146. Zipfel PF, Edey M, Heinen S, et al. Deletion of complement factor H–related genes cfhr1 and cfhr3 is associated with atypical hemolytic uremic syndrome. PLoS Genet. 2007;3(3):e41
  147. Zipfel PF, Heinen S, Józsi M, et al. Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol. 2006;43(1–2):97–106
  148. Zipfel PF, Misselwitz J, Licht C, et al. The role of defective complement control in hemolytic uremic syndrome. Semin Thromb Hemost. 2006;32(2):146–154
  149. Zipfel PF, Skerka C. Complement dysfunction in hemolytic uremic syndrome. Curr Opin Rheumatol. 2006;18(5):548–555
  150. Zipfel PF, Skerka C, Caprioli J, et al. Complement factor H and hemolytic uremic syndrome. Int Immunopharmacol. 2001;1(3):461–468

 Supported in part by the Elizabeth C. King Trust, in collaboration with the Wills Eye Institute, Philadelphia, PA. Gregory Hageman, PhD, Helga Magargal, MD, Larry Magargal, MD, David Pao, MD, and Drs Carol and Jerry Shields provided helpful discussions. Drs Carol and Jerry Shields provided clinical photographs. The Foundation also acknowledges the support of the residents of Pennswood Village and Twining Village who help to support eye research. Christine Skerka and Paul Barlow provided assistance with some aspects of the text and figures related to Factor H. None of the authors have a commercial interest in any of the pharmaceuticals mentioned in the text or figures.

PII: S0039-6257(09)00300-2

doi: 10.1016/j.survophthal.2009.11.001

Survey of Ophthalmology
Volume 55, Issue 3 , Pages 227-246 , May 2010