The Complement System in AMD

  • P. Charbel IssaEmail author
  • N. V. Chong
  • H. P. N. Scholl


Age-related macular degeneration (AMD) is a complex disease with genetic, environmental, and demo­graphic risk factors (see previous chapters). In recent years, there has been growing evidence that the inflammatory processes, including dysregulation of the complement system, play a major role in the pathogenesis of AMD. The discovery of genetic polymorphisms in genes coding for complement proteins that affect patients’ susceptibility to AMD propelled research in establishing the complement system as a key component in the pathogenesis of AMD [1].


Polypoidal Choroidal Vasculopathy Geographic Atrophy Retinal Angiomatous Proliferation Y402H Variant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



A similar text has been published in Graefe’s Archive for Clinical and Experimental Ophthalmology (Charbel Issa, Chong, Scholl (2011) The Significance of the Complement System for the Pathogenesis of Age-Related Macular Degeneration – Current Evidence and Translation into Clinical Application. This work was supported by the Euro­­pean Commission, Seventh European Community Framework Program, Marie Curie Intra-European Fellowship (237 238) to PCI; the Wynn-Gund Translational Research Acceleration Program Enhanced Research and Clinical Training Award, National Neuro­vision Research Institute (NNRI) – Foundation Fighting Blindness (FFB; NNCD-CL-0310.0049-JHU-WG) to HPNS; and the Macular Degeneration Research Award, American Health Assistance Foundation (AHAF; M2010042) to HPNS.


  1. 1.
    Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, Hancox LS, Hu J, Ebright JN, Malek G, Hauser MA, Bowes RC, Bok D, Hageman GS, Johnson LV (2009) The pivotal role of the complement system in ageing and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29:95–112PubMedCrossRefGoogle Scholar
  2. 2.
    Dunkelberger JR, Song WC (2010) Complement and its role in innate and adaptive immune responses. Cell Res 20:34–50PubMedCrossRefGoogle Scholar
  3. 3.
    Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, Kamei M, Hasan A, Yan L, Rayborn ME, Salomon RG, Hollyfield JG (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 99:14682–14687PubMedCrossRefGoogle Scholar
  4. 4.
    Johnson LV, Leitner WP, Staples MK, Anderson DH (2001) Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res 73:887–896PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson DH, Mullins RF, Hageman GS, Johnson LV (2002) A role for local inflammation in the formation of drusen in the ageing eye. Am J Ophthalmol 134:411–431PubMedCrossRefGoogle Scholar
  6. 6.
    Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) Drusen associated with ageing and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 14:835–846PubMedGoogle Scholar
  7. 7.
    Hageman GS, Luthert PJ, Chong NHV, Johnson LV, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in ageing and age-related macular degeneration. Prog Retin Eye Res 20:705–732PubMedCrossRefGoogle Scholar
  8. 8.
    Mullins RF, Aptsiauri N, Hageman GS (2001) Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye 15:390–395PubMedCrossRefGoogle Scholar
  9. 9.
    Yuan X, Gu X, Crabb JS, Yue X, Shadrach K, Hollyfield JG, Crabb JW (2010) Quantitative proteomics: comparison of the macular Bruch membrane/choroid complex from age-related macular degeneration and normal eyes. Mol Cell Proteomics 9:1031–1046PubMedCrossRefGoogle Scholar
  10. 10.
    Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, Sangiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389PubMedCrossRefGoogle Scholar
  11. 11.
    Clark SJ, Perveen R, Hakobyan S, Morgan BP, Sim RB, Bishop PN, Day AJ (2010) Impaired binding of the AMD-associated complement factor H 402H allotype to Bruch’s membrane in human retina. J Biol Chem 285(39):30192–30202PubMedCrossRefGoogle Scholar
  12. 12.
    Seddon JM, Ajani UA, Mitchell BD (1997) Familial aggregation of age-related maculopathy. Am J Ophthalmol 123:199–206PubMedGoogle Scholar
  13. 13.
    Seddon JM, Cote J, Page WF, Aggen SH, Neale MC (2005) The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 123:321–327PubMedCrossRefGoogle Scholar
  14. 14.
    de Jong PT, Klaver CC, Wolfs RC, Assink JJ, Hofman A (1997) Familial aggregation of age-related maculopathy. Am J Ophthalmol 124:862–863PubMedGoogle Scholar
  15. 15.
    Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT (1998) Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophth­almol 116:1646–1651PubMedGoogle Scholar
  16. 16.
    Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–421PubMedCrossRefGoogle Scholar
  17. 17.
    Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424PubMedCrossRefGoogle Scholar
  18. 18.
    Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102:7227–7232PubMedCrossRefGoogle Scholar
  19. 19.
    Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Borncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M (2008) Systemic complement activation in age-related macular degeneration. PLoS One 3:e2593PubMedCrossRefGoogle Scholar
  20. 20.
    Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM (2009) Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci 50:5818–5827PubMedCrossRefGoogle Scholar
  21. 21.
    Hecker LA, Edwards AO, Ryu E, Tosakulwong N, Baratz KH, Brown WL, Charbel Issa P, Scholl HP, Pollok-Kopp B, Schmid-Kubista KE, Bailey KR, Oppermann M (2010) Genetic control of the alternative pathway of complement in humans and age-related macular degeneration. Hum Mol Genet 19:209–215PubMedCrossRefGoogle Scholar
  22. 22.
    Skerka C, Lauer N, Weinberger AA, Keilhauer CN, Suhnel J, Smith R, Schlotzer-Schrehardt U, Fritsche L, Heinen S, Hartmann A, Weber BH, Zipfel PF (2007) Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 44:3398–3406PubMedCrossRefGoogle Scholar
  23. 23.
    Laine M, Jarva H, Seitsonen S, Haapasalo K, Lehtinen MJ, Lindeman N, Anderson DH, Johnson PT, Jarvela I, Jokiranta TS, Hageman GS, Immonen I, Meri S (2007) Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J Immunol 178:3831–3836PubMedGoogle Scholar
  24. 24.
    Ormsby RJ, Ranganathan S, Tong JC, Griggs KM, Dimasi DP, Hewitt AW, Burdon KP, Craig JE, Hoh J, Gordon DL (2008) Functional and structural implications of the complement factor H Y402H polymorphism associated with age-related macular degeneration. Invest Oph­thalmol Vis Sci 49:1763–1770PubMedCrossRefGoogle Scholar
  25. 25.
    Sjoberg AP, Trouw LA, Clark SJ, Sjolander J, Heinegard D, Sim RB, Day AJ, Blom AM (2007) The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells. J Biol Chem 282:10894–10900PubMedCrossRefGoogle Scholar
  26. 26.
    Herbert AP, Deakin JA, Schmidt CQ, Blaum BS, Egan C, Ferreira VP, Pangburn MK, Lyon M, Uhrin D, Barlow PN (2007) 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 282:18960–18968PubMedCrossRefGoogle Scholar
  27. 27.
    Clark SJ, Higman VA, Mulloy B, Perkins SJ, Lea SM, Sim RB, Day AJ (2006) 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 281:24713–24720PubMedCrossRefGoogle Scholar
  28. 28.
    Yu J, Wiita P, Kawaguchi R, Honda J, Jorgensen A, Zhang K, Fischetti VA, Sun H (2007) Biochemical analysis of a common human polymorphism associated with age-related macular degeneration. Biochemistry 46:8451–8461PubMedCrossRefGoogle Scholar
  29. 29.
    Tortajada A, Montes T, Martinez-Barricarte R, Morgan BP, Harris CL, de Cordoba SR (2009) The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity. Hum Mol Genet 18:3452–3461PubMedCrossRefGoogle Scholar
  30. 30.
    Zhou J, Jang YP, Kim SR, Sparrow JR (2006) Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci USA 103:16182–16187PubMedCrossRefGoogle Scholar
  31. 31.
    Wang AL, Lukas TJ, Yuan M, Du N, Handa JT, Neufeld AH (2009) Changes in retinal pigment epithelium related to cigarette smoke: possible relevance to smoking as a risk factor for age-related macular degeneration. PLoS One 4:e5304PubMedCrossRefGoogle Scholar
  32. 32.
    Hollyfield JG, Perez VL, Salomon RG (2010) A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. Mol Neurobiol 41:290–298PubMedCrossRefGoogle Scholar
  33. 33.
    Chen H, Liu B, Lukas TJ, Neufeld AH (2008) The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration. PLoS One 3:e2339PubMedCrossRefGoogle Scholar
  34. 34.
    Wasmuth S, Lueck K, Baehler H, Lommatzsch A, Paulei­khoff D (2009) Increased vitronectin production by complement-stimulated human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 50:5304–5309PubMedCrossRefGoogle Scholar
  35. 35.
    Thurman JM, Renner B, Kunchithapautham K, Ferreira VP, Pangburn MK, Ablonczy Z, Tomlinson S, Holers VM, Rohrer B (2009) Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem 284:16939–16947PubMedCrossRefGoogle Scholar
  36. 36.
    Chen M, Forrester JV, Xu H (2007) Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res 84:635–645PubMedCrossRefGoogle Scholar
  37. 37.
    Chen M, Muckersie E, Robertson M, Forrester JV, Xu H (2008) Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp Eye Res 87:543–550PubMedCrossRefGoogle Scholar
  38. 38.
    Coffey PJ, Gias C, McDermott CJ, Lundh P, Pickering MC, Sethi C, Bird A, Fitzke FW, Maass A, Chen LL, Holder GE, Luthert PJ, Salt TE, Moss SE, Greenwood J (2007) Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc Natl Acad Sci USA 104:16651–16656PubMedCrossRefGoogle Scholar
  39. 39.
    Nitsch D, Douglas I, Smeeth L, Fletcher A (2008) Age-related macular degeneration and complement activation-related diseases: a population-based case-control study. Ophthalmology 115:1904–1910PubMedCrossRefGoogle Scholar
  40. 40.
    Zipfel PF (2009) Complement and immune defense: from innate immunity to human diseases. Immunol Lett 126:1–7PubMedCrossRefGoogle Scholar
  41. 41.
    McAvoy CE, Silvestri G (2005) Retinal changes associated with type 2 glomerulonephritis. Eye (Lond) 19:985–989CrossRefGoogle Scholar
  42. 42.
    Duvall-Young J, MacDonald MK, McKechnie NM (1989) Fundus changes in (type II) mesangiocapillary glomerulonephritis simulating drusen: a histopathological report. Br J Ophthalmol 73:297–302PubMedCrossRefGoogle Scholar
  43. 43.
    Duvall-Young J, Short CD, Raines MF, Gokal R, Lawler W (1989) Fundus changes in mesangiocapillary glomerulonephritis type II: clinical and fluorescein angiographic findings. Br J Ophthalmol 73:900–906PubMedCrossRefGoogle Scholar
  44. 44.
    Boon CJ, van de Kar NC, Klevering BJ, Keunen JE, Cremers FP, Klaver CC, Hoyng CB, Daha MR, den Hollander AI (2009) The spectrum of phenotypes caused by variants in the CFH gene. Mol Immunol 46:1573–1594PubMedCrossRefGoogle Scholar
  45. 45.
    Sepp T, Khan JC, Thurlby DA, Shahid H, Clayton DG, Moore AT, Bird AC, Yates JR (2006) Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 47:536–540PubMedCrossRefGoogle Scholar
  46. 46.
    Magnusson KP, Duan S, Sigurdsson H, Petursson H, Yang Z, Zhao Y, Bernstein PS, Ge J, Jonasson F, Stefansson E, Helgadottir G, Zabriskie NA, Jonsson T, Bjornsson A, Thorlacius T, Jonsson PV, Thorleifsson G, Kong A, Stefansson H, Zhang K, Stefansson K, Gulcher JR (2006) CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. PLoS Med 3:e5PubMedCrossRefGoogle Scholar
  47. 47.
    Francis PJ, Schultz DW, Hamon S, Ott J, Weleber RG, Klein ML (2007) Haplotypes in the complement factor H (CFH) gene: associations with drusen and advanced age-related macular degeneration. PLoS One 2:e1197PubMedCrossRefGoogle Scholar
  48. 48.
    Seddon JM, George S, Rosner B, Klein ML (2006) CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 61:157–165PubMedCrossRefGoogle Scholar
  49. 49.
    Shuler RK Jr, Schmidt S, Gallins P, Hauser MA, Scott WK, Caldwell J, Agarwal A, Haines JL, Pericak-Vance MA, Postel EA (2008) Peripheral reticular pigmentary change is associated with complement factor H polymorphism (Y402H) in age-related macular degeneration. Ophthalmology 115:520–524PubMedCrossRefGoogle Scholar
  50. 50.
    Wegscheider BJ, Weger M, Renner W, Steinbrugger I, Marz W, Mossbock G, Temmel W, El-Shabrawi Y, Schmut O, Jahrbacher R, Haas A (2007) Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration. Ophthal­mology 114:738–742PubMedCrossRefGoogle Scholar
  51. 51.
    Leveziel N, Zerbib J, Richard F, Querques G, Morineau G, Fremeaux-Bacchi V, Coscas G, Soubrane G, Benlian P, Souied EH (2008) Genotype-phenotype correlations for exudative age-related macular degeneration associated with homozygous HTRA1 and CFH genotypes. Invest Ophthalmol Vis Sci 49:3090–3094PubMedCrossRefGoogle Scholar
  52. 52.
    Brantley MA Jr, Edelstein SL, King JM, Apte RS, Kymes SM, Shiels A (2007) Clinical phenotypes associated with the complement factor H Y402H variant in age-related macular degeneration. Am J Ophthalmol 144:404–408PubMedCrossRefGoogle Scholar
  53. 53.
    Andreoli MT, Morrison MA, Kim BJ, Chen L, Adams SM, Miller JW, DeAngelis MM, Kim IK (2009) Comprehensive analysis of complement factor H and LOC387715/ARMS2/HTRA1 variants with respect to phenotype in advanced age-related macular degeneration. Am J Ophthalmol 148:869–874PubMedCrossRefGoogle Scholar
  54. 54.
    Leveziel N, Puche N, Richard F, Somner JE, Zerbib J, Bastuji-Garin S, Cohen SY, Korobelnik JF, Sahel J, Soubrane G, Benlian P, Souied EH (2010) Genotypic influences on severity of exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 51:2620–2625PubMedCrossRefGoogle Scholar
  55. 55.
    Grassi MA, Folk JC, Scheetz TE, Taylor CM, Sheffield VC, Stone EM (2007) Complement factor H polymorphism p.Tyr402His and cuticular Drusen. Arch Ophthalmol 125:93–97PubMedCrossRefGoogle Scholar
  56. 56.
    Boon CJ, Klevering BJ, Hoyng CB, Zonneveld-Vrieling MN, Nabuurs SB, Blokland E, Cremers FP, den Hollander AI (2008) Basal laminar drusen caused by compound heterozygous variants in the CFH gene. Am J Hum Genet 82:516–523PubMedCrossRefGoogle Scholar
  57. 57.
    Ciardella AP, Donsoff IM, Huang SJ, Costa DL, Yannuzzi LA (2004) Polypoidal choroidal vasculopathy. Surv Ophthalmol 49:25–37PubMedCrossRefGoogle Scholar
  58. 58.
    Laude A, Cackett PD, Vithana EN, Yeo IY, Wong D, Koh AH, Wong TY, Aung T (2010) Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration: same or different disease? Prog Retin Eye Res 29:19–29PubMedCrossRefGoogle Scholar
  59. 59.
    Kondo N, Honda S, Kuno S, Negi A (2009) Coding variant I62V in the complement factor H gene is strongly associated with polypoidal choroidal vasculopathy. Ophthalmology 116:304–310PubMedCrossRefGoogle Scholar
  60. 60.
    Lee KY, Vithana EN, Mathur R, Yong VH, Yeo IY, Thalamuthu A, Lee MW, Koh AH, Lim MC, How AC, Wong DW, Aung T (2008) Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 49:2613–2619PubMedCrossRefGoogle Scholar
  61. 61.
    Hayashi H, Yamashiro K, Gotoh N, Nakanishi H, Nakata I, Tsujikawa A, Otani A, Saito M, Iida T, Matsuo K, Tajima K, Yamada R, Yoshimura N (2010) CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci. 51:5914–5919Google Scholar
  62. 62.
    Lima LH, Schubert C, Ferrara DC, Merriam JE, Imamura Y, Freund KB, Spaide RF, Yannuzzi LA, Allikmets R (2010) Three major loci involved in age-related macular degeneration are also associated with polypoidal choroidal vasculopathy. Ophthalmology 117:1567–1570PubMedCrossRefGoogle Scholar
  63. 63.
    Farwick A, Wellmann J, Stoll M, Pauleikhoff D, Hense HW (2010) Susceptibility genes and progression in age-related maculopathy: a study of single eyes. Invest Ophthalmol Vis Sci 51:731–736PubMedCrossRefGoogle Scholar
  64. 64.
    Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP, Boekhoorn SS, Vingerling JR, Hofman A, Oostra BA, Uitterlinden AG, Stijnen T, van Duijn CM, de Jong PT (2006) Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 296:301–309PubMedCrossRefGoogle Scholar
  65. 65.
    Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML (2007) Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 297:1793–1800PubMedCrossRefGoogle Scholar
  66. 66.
    Baird PN, Robman LD, Richardson AJ, Dimitrov PN, Tikellis G, McCarty CA, Guymer RH (2008) Gene-environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection. Hum Mol Genet 17:1299–1305PubMedCrossRefGoogle Scholar
  67. 67.
    Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B (2009) Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 50:2044–2053PubMedCrossRefGoogle Scholar
  68. 68.
    Francis PJ, Hamon SC, Ott J, Weleber RG, Klein ML (2009) Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet 46:300–307PubMedCrossRefGoogle Scholar
  69. 69.
    Scholl HP, Fleckenstein M, Fritsche LG, Schmitz-Valckenberg S, Gobel A, Adrion C, Herold C, Keilhauer CN, Mackensen F, Mossner A, Pauleikhoff D, Weinberger AW, Mansmann U, Holz FG, Becker T, Weber BH (2009) CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD. PLoS One 4:e7418PubMedCrossRefGoogle Scholar
  70. 70.
    Klein ML, Ferris FL 3rd, Francis PJ, Lindblad AS, Chew EY, Hamon SC, Ott J (2010) Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology. 117:1554–1559Google Scholar
  71. 71.
    Age-Related Eye Disease Study Research Group (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 119:1417–1436CrossRefGoogle Scholar
  72. 72.
    Cho E, Hung S, Willett WC, Spiegelman D, Rimm EB, Seddon JM, Colditz GA, Hankinson SE (2001) Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr 73:209–218PubMedGoogle Scholar
  73. 73.
    Chong EWT, Kreis AJ, Wong TY, Simpson JA, Guymer RH (2008) Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration – a systematic review and meta-analysis. Arch Ophthalmol 126:826–833PubMedCrossRefGoogle Scholar
  74. 74.
    Chua B, Flood V, Rochtchina E, Wang JJ, Smith W, Mitchell P (2006) Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol 124:981–986PubMedCrossRefGoogle Scholar
  75. 75.
    Klein ML, Francis PJ, Rosner B, Reynolds R, Hamon SC, Schultz DW, Ott J, Seddon JM (2008) CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 115:1019–1025PubMedCrossRefGoogle Scholar
  76. 76.
    Ho L, van Leeuwen R, Witteman JCM, van Duijn CM, Uitterlinden AG, Hofman A, de Jong PTVM, Vingerling JR, Klaver CC (2011) Can dietary antioxidants reduce the genetic 1 risk of age-related macular degeneration? The Rotterdam study. Arch Ophthalmol 129(6):758–766PubMedCrossRefGoogle Scholar
  77. 77.
    Conley YP, Jakobsdottir J, Mah T, Weeks DE, Klein R, Kuller L, Ferrell RE, Gorin MB (2006) CFH, ELOVL4, PLEKHA1, and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet 15(21):3206–3218PubMedCrossRefGoogle Scholar
  78. 78.
    Wang JJ, Rochtchina E, Smith W, Klein R, Klein BE, Joshi T, Sivakumaran TA, Iyengar S, Mitchell P (2009) Combined effects of complement factor H genotypes, fish consumption, and inflammatory markers on long-term risk for age-related macular degeneration in a cohort. Am J Epidemiol 169:633–641PubMedCrossRefGoogle Scholar
  79. 79.
    Schaumberg DA, Hankinson SE, Guo Q, Rimm E, Hunter DJ (2007) A prospective study of 2 major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors. Arch Ophthalmol 125:55–62PubMedCrossRefGoogle Scholar
  80. 80.
    DeAngelis MM, Ji F, Kim IK, Adams S, Capone A Jr, Ott J, Miller JW, Dryja TP (2007) Cigarette smoking, CFH, APOE, ELOVL4, and risk of neovascular age-related macular degeneration. Arch Ophthalmol 125:49–54PubMedCrossRefGoogle Scholar
  81. 81.
    Hughes AE, Orr N, Patterson C, Esfandiary H, Hogg R, McConnell V, Silvestri G, Chakravarthy U (2007) Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking. PLoS Med 4:e355PubMedCrossRefGoogle Scholar
  82. 82.
    Schlingemann RO, Witmer AN (2009) Treatment of retinal diseases with VEGF antagonists. Prog Brain Res 175:253–267PubMedCrossRefGoogle Scholar
  83. 83.
    Brantley MA Jr, Fang AM, King JM, Tewari A, Kymes SM, Shiels A (2007) Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 114:2168–2173PubMedCrossRefGoogle Scholar
  84. 84.
    Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr (2009) Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 93:610–613PubMedCrossRefGoogle Scholar
  85. 85.
    Goverdhan SV, Hannan S, Newsom RB, Luff AJ, Griffiths H, Lotery AJ (2008) An analysis of the CFH Y402H genotype in AMD patients and controls from the UK, and response to PDT treatment. Eye (Lond) 22:849–854CrossRefGoogle Scholar
  86. 86.
    Brantley MA Jr, Edelstein SL, King JM, Plotzke MR, Apte RS, Kymes SM, Shiels A (2009) Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy. Eye (Lond) 23:626–631CrossRefGoogle Scholar
  87. 87.
    Feng X, Xiao J, Longville B, Tan AX, Wu XN, Cooper MN, McAllister IL, Isaacs T, Palmer LJ, Constable IJ (2009) Complement factor H Y402H and C-reactive protein polymorphism and photodynamic therapy response in age-related macular degeneration. Ophthalmology 116:1908–1912PubMedCrossRefGoogle Scholar
  88. 88.
    Seitsonen SP, Jarvela IE, Meri S, Tommila PV, Ranta PH, Immonen IJ (2007) The effect of complement factor H Y402H polymorphism on the outcome of photodynamic therapy in age-related macular degeneration. Eur J Ophth­almol 17:943–949PubMedGoogle Scholar
  89. 89.
    Hakobyan S, Harris CL, Tortajada A, de Goicochea JE, Garcia-Layana A, Fernandez-Robredo P, de Rodriguez CS, Morgan BP (2008) 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 49:1983–1990PubMedCrossRefGoogle Scholar
  90. 90.
    Kelly U, Rickman CB, Postel EA, Hauser MA, Hageman GS, Arshavsky VY, Skiba NP (2009) 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 50:1540–1545PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • P. Charbel Issa
    • 1
    Email author
  • N. V. Chong
    • 2
  • H. P. N. Scholl
    • 3
  1. 1.Department of OphthalmologyUniversity of BonnBonnGermany
  2. 2.Oxford Eye HospitalUniversity of OxfordOxfordUK
  3. 3.Wilmer Eye Institute, Johns Hopkins UniversityBaltimoreUSA

Personalised recommendations