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REVIEW ARTICLE

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

, , &
Pages 450-471 | Published online: 08 Jul 2009

References

  • Uhlmann R. F., Larson E. B., Koepsell T. D., Rees T. S., Duckert L. G. Visual impairment and cognitive dysfunction in Alzheimer's disease. J Gen Intern Med 1991; 6: 126–32
  • Lin M. Y., Gutierrez P. R., Stone K. L., Yaffe K., Ensrud K. E., Fink H. A., et al. Vision impairment and combined vision and hearing impairment predict cognitive and functional decline in older women. J Am Geriatr Soc 2004; 52: 1996–2002
  • Rovner B. W., Casten R. J., Tasman W. S. Effect of depression on vision function in age‐related macular degeneration. Arch Ophthalmol 2002; 120: 1041–4
  • Abyad A. In‐office screening for age‐related hearing and vision loss. Geriatrics 1997; 52: 45–6; 51–4; 57
  • Berman K., Brodaty H. Psychosocial effects of age‐related macular degeneration. Int Psychogeriatr 2006; 8: 1–14
  • Taylor H., Guymer R., Keeffe J. The Impact of Age‐Related Macular Degeneration. University of Melbourne, Melbourne 2006; 1–72, Access Economics Pty Limited
  • Sunness J. S. The natural history of geographic atrophy, the advanced atrophic form of age‐related macular degeneration. Mol Vis 1999; 5: 25
  • Magnitude and causes of visual impairment. World Health Organization, Fact Sheet No 282.
  • Resnikoff S., Pascolini D., Etya'ale D., Kocur I., Pararajasegaram R., Pokharel G. P., et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004; 82: 844–51
  • Klein R., Peto T., Bird A., Vannewkirk M. R. The epidemiology of age‐related macular degeneration. Am J Ophthalmol 2004; 137: 486–95
  • Smith W., Assink J., Klein R., Mitchell P., Klaver C., Klein B., et al. Risk factors for age‐related macular degeneration: Pooled findings from three continents. Ophthalmology 2001; 108: 697–704
  • Mitchell P., Smith W., Attebo K., Wang J. Prevalence of age‐related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 1995; 102: 1450–60
  • VanNewkirk M., Nanjan M., Wang J., Mitchell P., Taylor H., McCarty C. The prevalence of age‐related maculopathy: the visual impairment project. Ophthalmology 2000; 107: 1593–600
  • Wolfs R. C., Borger P. H., Ramrattan R. S., Klaver C. C., Hulsman C. A., Hofman A., et al. Changing views on open‐angle glaucoma: definitions and prevalences—The Rotterdam Study. Invest Ophthalmol Vis Sci 2000; 41: 3309–21
  • Mitchell P., Wang J. J., Foran S., Smith W. Five‐year incidence of age‐related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology 2002; 109: 1092–7
  • Friedman D. S., O'Colmain B. J., Munoz B., Tomany S. C., McCarty C., de Jong P. T., et al. Prevalence of age‐related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564–72
  • Taylor H. R., Keeffe J. E., Vu H. T., Wang J. J., Rochtchina E., Pezzullo M. L., et al. Vision loss in Australia. Med J Aust 2005; 182: 565–8
  • Jonasson F., Arnarsson A., Peto T., Sasaki H., Sasaki K., Bird A. C. 5‐year incidence of age‐related maculopathy in the Reykjavik Eye Study. Ophthalmology 2005; 112: 132–8
  • Andersen N. Age‐related macular degeneration among the Inuit in Greenland. Int J Circumpolar Health 2004; 63(Suppl 2)320–3
  • Vingerling J. R., Dielemans I., Hofman A., Grobbee D. E., Hijmering M., Kramer C. F., et al. The prevalence of age‐related maculopathy in the Rotterdam Study. Ophthalmology 1995; 102: 205–10
  • Krishnaiah S., Das T., Nirmalan P. K., Nutheti R., Shamanna B. R., Rao G. N., et al. Risk factors for age‐related macular degeneration: findings from the Andhra Pradesh eye disease study in South India. Invest Ophthalmol Vis Sci 2005; 46: 4442–9
  • Munoz B., Klein R., Rodriguez J., Snyder R., West S. K. Prevalence of age‐related macular degeneration in a population‐based sample of Hispanic people in Arizona: Proyecto VER. Arch Ophthalmol 2005; 123: 1575–80
  • Leske M. C., Wu S. Y., Hennis A., Nemesure B., Yang L., Hyman L., et al. Nine‐year incidence of age‐related macular degeneration in the Barbados Eye Studies. Ophthalmology 2006; 113: 29–35
  • Wong T. Y., Loon S. C., Saw S. M. The epidemiology of age related eye diseases in Asia. Br J Ophthalmol 2006; 90: 506–11
  • Klein R., Davis M. D., Magli Y. L., Segal P., Klein B. E., Hubbard L. The Wisconsin age‐related maculopathy grading system. Ophthalmology 1991; 98: 1128–34
  • Age‐Related Eye Disease Study Research Group. The Age‐Related Eye Disease Study (AREDS): design implications. AREDS report no. 1., Control Clin Trials. 20. 573–600
  • Davis M. D., Gangnon R. E., Lee L. Y., Hubbard L. D., Klein B. E., Klein R., et al. The Age‐Related Eye Disease Study severity scale for age‐related macular degeneration: AREDS Report No.17. Arch Ophthalmol 2005; 123: 1484–98
  • Ferris F. L., Davis M. D., Clemons T. E., Lee L. Y., Chew E. Y., Lindblad A. S., et al. A simplified severity scale for age‐related macular degeneration: AREDS Report No.18. Arch Ophthalmol 2005; 123: 1570–4
  • Wray S., Kuwabara T., Sanderson P. Menkes' kinky hair disease: a light and electron microscopic study of the eye. Invest Ophthalmol 1976; 15: 128–38
  • Abugreen S., Muldrew K. A., Stevenson M. R., VanLeeuwen R., DeJong P. T., Chakravarthy U. CNV subtype in first eyes predicts severity of ARM in fellow eyes. Br J Ophthalmol 2003; 87: 307–11
  • Clemons T. E., Milton R. C., Klein R., Seddon J. M., Ferris F. L., 3rd. Risk factors for the incidence of Advanced Age‐Related Macular Degeneration in the Age‐Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology 2005; 112: 533–9
  • Thornton J., Edwards R., Mitchell P., Harrison R. A., Buchan I., Kelly S. P. Smoking and age‐related macular degeneration: a review of association. Eye 2005; 19: 935–44
  • Age‐Related Eye Disease Study Research Group. 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 2001; 119: 1417–36
  • Choroidal neovascularization in the Choroidal Neovascularization Prevention Trial, The Choroidal Neovascularization Prevention Trial Research Group. Ophthalmology 1998; 105: 1364–72
  • Complications of Age‐Related Macular Degeneration Prevention Trial Study Group. The Complications of Age‐Related Macular Degeneration Prevention Trial (CAPT): rationale, design and methodology. Clin Trials 2004; 1: 91–107
  • Friberg T. R., Musch D. C., Lim J. I., Morse L., Freeman W., Sinclair S. Prophylactic treatment of age‐related macular degeneration report number 1: 810‐nanometer laser to eyes with drusen. Unilaterally eligible patients. Ophthalmology 2006; 113: 622 e1
  • Prenner J. L., Rosenblatt B. J., Tolentino M. J., Ying G. S., Javornik N. B., Maguire M. G., et al. Risk factors for choroidal neovascularization and vision loss in the fellow eye study of CNVPT. Retina 2003; 23: 307–14
  • Friberg T. R., the PTAMD Study Group. The Prophylactic Treatment of AMD Multi‐Centered Trial (PTAMD): Results From the Bilateral Study Arm. Invest Ophthalmol Vis Sci 2006; 47, E‐Abstract 3538
  • Argon laser photocoagulation for neovascular maculopathy, Three‐year results from randomized clinical trials. Macular Photocoagulation Study Group. Arch Ophthalmol 1986; 104: 694–701
  • Krypton laser photocoagulation for neovascular lesions of age‐related macular degeneration, Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1990; 108: 816–24
  • Laser photocoagulation of subfoveal neovascular lesions in age‐related macular degeneration, Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1991; 109: 1220–31
  • Han D. P., Folk J. C., Bratton A. R. Visual loss after successful photocoagulation of choroidal neovascularization. Ophthalmology 1988; 95: 1380–4
  • Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesions of age‐related macular degeneration, Macular Photocoagulation Study Group. Arch Ophthalmol 1990; 108: 825–31
  • Freund K. B., Yannuzzi L. A., Sorenson J. A. Age‐related macular degeneration and choroidal neovascularization. Am J Ophthalmol 1993; 115: 786–91
  • Bressler N. M., Bressler S. B., Childs A. L., Haller J. A., Hawkins B. S., Lewis H., et al. Surgery for hemorrhagic choroidal neovascular lesions of age‐related macular degeneration: ophthalmic findings: SST report no. 13. Ophthalmology 2004; 111: 1993–2006
  • Hawkins B. S., Bressler N. M., Miskala P. H., Bressler S. B., Holekamp N. M., Marsh M. J., et al. Surgery for subfoveal choroidal neovascularization in age‐related macular degeneration: ophthalmic findings: SST report no. 11. Ophthalmology 2004; 111: 1967–80
  • Machemer R., Steinhorst U. H. Retinal separation, retinotomy, and macular relocation: II. A surgical approach for age‐related macular degeneration? Graefes Arch Clin Exp Ophthalmol 1993; 231: 635–41
  • de Juan E., Jr., Loewenstein A., Bressler N. M., Alexander J. Translocation of the retina for management of subfoveal choroidal neovascularization II: a preliminary report in humans. Am J Ophthalmol 1998; 125: 635–46
  • Photodynamic therapy of subfoveal choroidal neovascularization in age‐related macular degeneration with verteporfin: one‐year results of 2 randomized clinical trials—TAP report. Treatment of age‐related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol 1999; 117: 1329–45
  • Schmidt‐Erfurth U., Hasan T. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age‐related macular degeneration. Surv Ophthalmol 2000; 45: 195–214
  • Verteporfin In Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age‐related macular degeneration: two‐year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—verteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001; 131: 541–60
  • Bressler N. M., Arnold J., Benchaboune M., Blumenkranz M. S., Fish G. E., Gragoudas E. S., et al. Verteporfin therapy of subfoveal choroidal neovascularization in patients with age‐related macular degeneration: additional information regarding baseline lesion composition's impact on vision outcomes—TAP report No.3. Arch Ophthalmol 2002; 120: 1443–54
  • Stevenson M. R., Hart P. M., Chakravarthy U., Mackenzie G., Bird A. C., Owens S. L., et al. Visual functioning and quality of life in the SubFoveal Radiotherapy Study (SFRADS): SFRADS report 2. Br J Ophthalmol 2005; 89: 1045–51
  • Goverdhan S. V., Gibbs F. A., Lotery A. J. Radiotherapy for age‐related macular degeneration: no more pilot studies please. Eye 2005; 19: 1137–41
  • Marcus D. M., Peskin E., Maguire M., Weissgold D., Alexander J., Fine S., et al. The age‐related macular degeneration radiotherapy trial (AMDRT): one year results from a pilot study. Am J Ophthalmol 2004; 138: 818–28
  • Gragoudas E. S., Adamis A. P., Cunningham E. T., Jr., Feinsod M., Guyer D. R. Pegaptanib for neovascular age‐related macular degeneration. N Engl J Med 2004 30; 351: 2805–16
  • Heier JS., Shapiro H., Singh AA. Randomized, Controlled Phase III Study of Ranibizumab (LucentisTM) for Minimally Classic or Occult Neovascular Age‐Related Macular Degeneration: Two‐Year Efficacy Results of the MARINA Study. Invest Ophthalmol Vis Sci 2006; 47, E‐Abstract 2959
  • Rosenfeld P. J., Moshfeghi A. A., Puliafito C. A. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age‐related macular degeneration. Ophthalmic Surg Lasers Imaging 2005; 36: 331–5
  • Avery R. L., Pieramici D. J., Rabena M. D., Castellarin A. A., Nasir M. A., Giust M. J. Intravitreal bevacizumab (Avastin) for neovascular age‐related macular degeneration. Ophthalmology 2006; 113: 363–72 e5
  • Vinores S. A. Anecortave (Alcon Laboratories). IDrugs 2005; 8: 327–34
  • D'Amico D. J., Goldberg M. F., Hudson H., Jerdan J. A., Krueger D. S., Luna S. P., et al. Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age‐related macular degeneration: twelve‐month clinical outcomes. Ophthalmology 2003; 110: 2372–83, discussion 84–5
  • Spaide R. F., Sorenson J., Maranan L. Photodynamic therapy with verteporfin combined with intravitreal injection of triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2005; 112: 301–4
  • Quiram P. A., Gonzales C. R., Schwartz S. D. Severe steroid‐induced glaucoma following intravitreal injection of triamcinolone acetonide. Am J Ophthalmol 2006; 141: 580–2
  • Jonas J. B., Kreissig I., Spandau U. H., Harder B. Infectious and noninfectious endophthalmitis after intravitreal high‐dosage triamcinolone acetonide. Am J Ophthalmol 2006; 141: 579–80
  • Guymer R. H., Chiu A. W., Lim L., Baird P. N. HMG CoA reductase inhibitors (statins): do they have a role in age‐related macular degeneration?. Surv Ophthalmol 2005; 50: 194–206
  • Sarks S., Arnold J., Killingsworth M., Sarks J. Early drusen formation in the normal and aging eye and their relation to age‐related maculopathy: a clinicopathological study. Br J Ophthalmol 1999; 83: 358–68
  • McConnell V., Silvestri G. Age‐related macular degeneration. Ulster Med J 2005; 74: 82–92
  • Provis J. M., Penfold P. L., Cornish E. E., Sandercoe T. M., Madigan M. C. Anatomy and development of the macula: specialisation and the vulnerability to macular degeneration. Clin Exp Optom 2005; 88: 269–81
  • Donoso L. A., Kim D., Frost A., Callahan A., Hageman G. The role of inflammation in the pathogenesis of age‐related macular degeneration. Surv Ophthalmol 2006; 51: 137–52
  • Arnold J., Sarks S. Age related macular degeneration. Clin Evid 2004; 819–34
  • Hageman G., Mullins R. Molecular composition of drusen as related to substructural phenotype. Mol Vis 1999; 5: 28
  • Sarraf D., Gin T., Yu F., Brannon A., Owens S. L., Bird A. C. Long‐term drusen study. Retina 1999; 19: 513–9
  • Klein R., Klein B., Jensen S., Meuer S. The five‐year incidence and progression of age‐related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997; 104: 7–21
  • Spraul C., Grossniklaus H. Characteristics of drusen and Bruch's membrane in postmortem eyes with age‐related macular degeneration. Arch Ophthalmol 1997; 115: 267–73
  • Sarks J. P., Sarks S. H., Killingsworth M. C. Evolution of soft drusen in age‐related macular degeneration. Eye 1994; 8((Pt 3))269–83
  • Guymer R., Bird A. Bruch's membrane, drusen, and age‐related macular degeneration. The Retinal Pigment Epithelium, M Marmor, T Wolfensberger. Oxford University Press, New York 1998; 693–705
  • Zarbin M. A. Current concepts in the pathogenesis of age‐related macular degeneration. Arch Ophthalmol 2004 Apr; 122: 598–614
  • Sivaprasad S., Bailey T. A., Chong V. N. Bruch's membrane and the vascular intima: is there a common basis for age‐related changes and disease?. Clin Experiment Ophthalmol 2005; 33: 518–23
  • Marshall J., Hussain A., Starita C., Moore D., Patmore A. The Retinal Pigment Epithelium. Oxford University Press, New York 1998
  • Guymer R., Luthert P., Bird A. Changes in Bruch's membrane and related structures with age. Prog Retin Eye Res 1999; 18: 59–90
  • Hogan M., Alvarado J. Studies on the human macula. Aging changes in Bruch's membrane. Arch Ophthalmol 1967; 77: 410–20
  • Sarks S. H. Ageing and degeneration in the macular region: a clinico‐pathological study. Br J Ophthalmol 1976; 60: 324–41
  • Green W. R., McDonnell P. J., Yeo J. H. Pathologic features of senile macular degeneration. Ophthalmology 1985; 92: 615–27
  • Feeney‐Burns L., Ellersieck M. Age‐related changes in the ultrastructure of Bruch's membrane. Am J Ophthalmol 1985; 100: 686–97
  • Grindle C., Marshall J. Ageing changes in Bruch's membrane and their functional implications. Trans Ophthal Soc UK 1978; 98: 172–5
  • Pauleikhoff D., Sheraidah G., Marshall J., Bird A., Wessing A. Biochemical and histochemical analysis of age related lipid deposits in Bruch's membrane. Ophthalmologe 1994; 91: 730–4
  • Handa J. T., Verzijl N., Matsunaga H., Aotaki‐Keen A., Lutty G. A., te Koppele J. M., et al. Increase in the advanced glycation end product pentosidine in Bruch's membrane with age. Invest Ophthalmol Vis Sci 1999; 40: 775–9
  • Curcio C., Millican C., Bailey T., Kruth H. Accumulation of cholesterol with age in human Bruch's membrane. Invest Ophthalmol Vis Sci 2001; 42: 265–74
  • Kamei M., Hollyfield J. TIMP‐3 in Bruch's membrane: changes during aging and in age‐related macular degeneration. Invest Ophthalmol Vis Sci 1999; 40: 2367–75
  • Newsome D., Huh W., Green W. Bruch's membrane age‐related changes vary by region. Curr Eye Res 1987; 6: 1211–21
  • Ishibashi T., Murata T., Hangai M., Nagai R., Horiuchi S., Lopez P., et al. Advanced glycation end products in age‐related macular degeneration. Arch Ophthalmol 1998; 116: 1629–32
  • Hewitt A., Nakazawa K., Newsome D. Analysis of newly synthesized Bruch's membrane proteoglycans. Invest Ophthalmol Vis Sci 1989; 30: 478–86
  • Karwatowski W., Jeffries T., Duance V., Albon J., Bailey A., Easty D. Preparation of Bruch's membrane and analysis of the age‐related changes in the structural collagens. Br J Ophthalmol 1995; 79: 944–52
  • Haimovici R., Gantz D. L., Rumelt S., Freddo T. F., Small D. M. The lipid composition of drusen, Bruch's membrane, and sclera by hot stage polarizing light microscopy. Invest Ophthalmol Vis Sci 2001; 42: 1592–9
  • Li C. M., Chung B. H., Presley J. B., Malek G., Zhang X., Dashti N., et al. Lipoprotein‐like particles and cholesteryl esters in human Bruch's membrane: initial characterization. Invest Ophthalmol Vis Sci 2005; 46: 2576–86
  • Starita C., Hussain A., Pagliarini S., Marshall J. Hydrodynamics of ageing Bruch's membrane: implications for macular disease. Exp Eye Res 1996; 62: 565–72
  • Moore D., Clover G. The effect of age on the macromolecuar permeability of human Bruch's membrane. Invest Ophthalmol Vis Sci 2001; 42: 2970–5
  • Hussain A., Rowe L., Marshall J. Age‐related alterations in the diffusional transport of amino acids across the human Bruch's‐choroid complex. J Opt Soc Am A Opt Image Sci Vis 2002; 19: 166–72
  • Moore D., Hussain A., Marshall J. Age‐related variation in the hydraulic conductivity of Bruch's membrane. Invest Ophthalmol Vis Sci 1995; 36: 1290–7
  • Chong N. H., Keonin J., Luthert P. J., Frennesson C. I., Weingeist D. M., Wolf R. L., 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
  • Nackman G., Karkowski F., Halpern V., Gaetz H., Tilson M. Elastin degradation products induce adventitial angiogenesis in the Anidjar/Dobrin rat aneurysm model. Surgery 1997; 122: 39–44
  • Kamisato S., Uemura Y., Takami N., Okamoto K. Involvement of intracellular cyclic GMP and cyclic GMP‐dependent protein kinase in alpha‐elastin‐induced macrophage chemotaxis. J Biochem (Tokyo) 1997; 121: 862–7
  • Marshall J., Hussain A., Starita C., Moore D., Patmore A. Aging and Bruch's membrane. The Retinal Pigment Epithelium, M Marmor, T Wolfensberger. Oxford University Press, New York 1998; 669–92
  • Holz F., Sheraiadah G., Pauleikhoff D., Marshall J., Bird A. Analysis of lipid deposits extracted from human macular and peripheral Bruch's membrane. Arch Ophthalmol 1994; 112: 402–6
  • Pauleikhoff D., Harper C., Marshall J., Bird A. Aging changes in Bruch's membrane. Ophthalmology 1990; 97: 171–8
  • Anderson D., Ozaki S., Nealon M., Neitz J., Mullins R., Hageman G., 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
  • Farkas T., Sylvester V., Archer D., Altona M. The histochemistry of drusen. Am J Ophthalmol 1971; 71: 1206–15
  • Green W. R., Enger C. Age‐related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100: 1519–35
  • Kliffen M., van der Schaft T. L., Mooy C. M., de Jong P. T. Morphologic changes in age‐related maculopathy. Microsc Res Tech 1997; 36: 106–22
  • Feher J., Valu L. [On the structure of Bruch's membrane]. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1967; 173: 162–7
  • Loffler K. U., Lee W. R. Basal linear deposit in the human macula. Graefes Arch Clin Exp Ophthalmol 1986; 224: 493–501
  • van der Schaft T. L., de Bruijn W. C., Mooy C. M., Ketelaars D. A., de Jong P. T. Is basal laminar deposit unique for age‐related macular degeneration? [see comments]. Arch Ophthalmol 1991; 109: 420–5
  • van der Schaft T., Mooy C., de Bruijn W., Oron F., Mulder P., de Jong P. Histological features of age‐related macular degeneration. A statistical analysis. Ophthalmology 1992; 99: 278–86
  • Spraul C. W., Lang G. E., Grossniklaus H. E. Morphometric analysis of the choroid, Bruch's membrane, and retinal pigment epithelium in eyes with age‐related macular degeneration [see comments]. Invest Ophthalmol Vis Sci 1996; 37: 2724–35
  • Milam A. H., Curcio C. A., Cideciyan A. V., Saxena S., John S. K., Kruth H. S., et al. Dominant late‐onset retinal degeneration with regional variation of sub‐retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration. Ophthalmology 2000; 107: 2256–66
  • Kliffen M., Mooy C. M., Luider T. M., Huijmans J. G., Kerkvliet S., de Jong P. T. Identification of glycosaminoglycans in age‐related macular deposits. Arch Ophthalmol 1996; 114: 1009–14
  • Kliffen M., Mooy C. M., Luider T. M., de Jong P. T. Analysis of carbohydrate structures in basal laminar deposit in aging human maculae. Invest Ophthalmol Vis Sci 1994; 35: 2901–5
  • van der Schaft T., Mooy C., de Bruijn W., Bosman F., de Jong P. Immunohistochemical light and electron microscopy of basal laminar deposit. Graefes Arch Clin Exp Ophthalmol 1994; 232: 40–6
  • Knupp C., Amin S., Munro P., Luthert P., Squire J. Collagen VI assemblies in age‐related macular degeneration. J Struct Biol 2002; 139: 181–9
  • Curcio C. A., Presley J. B., Millican C. L., Medeiros N. E. Basal deposits and drusen in eyes with age‐related maculopathy: evidence for solid lipid particles. Exp Eye Res 2005; 80: 761–75
  • Sarks S., Van Driel D., Maxwell L., Killingsworth M. Softening of drusen and subretinal neovascularization. Trans Ophthalmol Soc U K 1980; 100: 414–22
  • Okubo A., Rosa R., Bunce C., Alexander R., Fan J., Bird A., et al. The relationships of age changes in retinal pigment epithelium and Bruch's membrane. Invest Ophthalmol Vis Sci 1999; 40: 443–9
  • Hogan M. Role of the retinal pigment epithelium in macular disease. Trans Am Acad Ophthalmol Otolaryngol 1972; 76: 64–80
  • Bird A. Pathophysiology of AMD. Age‐related macular degeneration: principles and practice, G. R Hampton, P. T Nelsen. Raven Press, New York 1992, Chapter 3
  • Dorey C., Wu G., Ebenstein D. Cell loss in the aging retina: Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci 1989; 30: 1691–9
  • Bird A. C. Bruch's membrane change with age. Br J Ophthalmol 1992; 76: 166–8
  • Katz M. L., Robison W. G., Jr. Age‐related changes in the retinal pigment epithelium of pigmented rats. Exp Eye Res 1984; 38: 137–51
  • Feeney‐Burns L., Hilderbrand E., Eldridge S. Aging human RPE: morphometric analysis of macular, equatorial and peripheral cells. Invest Ophthalmol Vis Sci 1984; 25: 195–200
  • Wing G., Blanchard G., Weiter J. Topography and age relationship of lipofuscin concentration in the RPE. Invest Ophthalmol Vis Sci 1978; 7: 601–7
  • Rozanowska M., Jarvis‐Evans J., Korytowski W., Boulton M. E., Burke J. M., Sarna T. Blue light‐induced reactivity of retinal age pigment. In vitro generation of oxygen‐reactive species. J Biol Chem 1995; 270: 18825–30
  • Holz F., Bellman C., Staudt S., Schutt F., Volcker H. Fundus autofluorescence and development of geographic atrophy in age‐related macular degeneration. Invest Ophthalmol Vis Sci 2001; 42: 1051–6
  • Katz M. L. Potential role of retinal pigment epithelial lipofuscin accumulation in age‐related macular degeneration. Arch Gerontol Geriatr 2002; 34: 359–70
  • Sparrow J. R., Boulton M. RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 2005; 80: 595–606
  • Ramrattan R., van der Schaft T., Mooy C., de Bruijn W., Mulder P., de Jong P. Morphometric analysis of Bruch's membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 1994; 35: 2857–64
  • McLeod D. S., Taomoto M., Otsuji T., Green W. R., Sunness J. S., Lutty G. A. Quantifying changes in RPE and choroidal vasculature in eyes with age‐related macular degeneration. Invest Ophthalmol Vis Sci 2002 Jun; 43: 1986–93
  • Midena E., Segato T., Blarzino M. C., Degli Angeli C. Macular drusen and the sensitivity of the central visual field. Doc Ophthalmol 1994; 88: 179–85
  • Curcio C., Medeiros N., Millican C. Photoreceptor loss in age‐related macular degeneration. Invest Ophthalmol Vis Sci 1996; 37: 1236–49
  • Jackson G. R., Owsley C. Visual dysfunction, neurodegenerative diseases, and aging. Neurol Clin 2003; 21: 709–28
  • Li J., Tso M. O., Lam T. T. Reduced amplitude and delayed latency in foveal response of multifocal electroretinogram in early age related macular degeneration. Br J Ophthalmol 2001; 85: 287–90
  • Owsley C., Jackson G. R., Cideciyan A. V., Huang Y., Fine S. L., Ho A. C., et al. Psychophysical evidence for rod vulnerability in age‐related macular degeneration. Invest Ophthalmol Vis Sci 2000; 41: 267–73
  • Jackson G. R., Owsley C., Curcio C. A. Photoreceptor degeneration and dysfunction in aging and age‐related maculopathy. Ageing Res Rev 2002; 1: 381–96
  • Owsley C., Jackson G. R., White M., Feist R., Edwards D. Delays in rod‐mediated dark adaptation in early age‐related maculopathy. Ophthalmology 2001; 108: 1196–202
  • Jackson G. R., McGwin G., Jr., Phillips J. M., Klein R., Owsley C. Impact of aging and age‐related maculopathy on activation of the a‐wave of the rod‐mediated electroretinogram. Invest Ophthalmol Vis Sci 2004; 45: 3271–8
  • Owsley C., McGwin G., Jackson G. R., Heimburger D. C., Piyathilake C. J., Klein R., et al. Effect of short‐term, high‐dose retinol on dark adaptation in aging and early age‐related maculopathy. Invest Ophthalmol Vis Sci 2006; 47: 1310–8
  • Stangos N., Voutas S., Topouzis F., Karampatakis V. Contrast sensitivity evaluation in eyes predisposed to age‐related macular degeneration and presenting normal visual acuity. Ophthalmologica 1995; 209: 194–8
  • Sunness J., Massof R., Johnson M., Bressler N., Bressler S., Fine S. Diminished foveal sensitivity may predict the development of advanced age‐related macular degeneration. Ophthalmology 1989; 96: 375–81
  • Kleiner R. C., Enger C., Alexander M. F., Fine S. L. Contrast sensitivity in age‐related macular degeneration. Arch Ophthalmol 1988; 106: 55–7
  • Sandberg M. A., Gaudio A. R. Slow photostress recovery and disease severity in age‐related macular degeneration. Retina 1995; 15: 407–12
  • Eisner A., Klein M. L., Zilis J. D., Watkins M. D. Visual function and the subsequent development of exudative age‐related macular degeneration. Invest Ophthalmol Vis Sci 1992; 33: 3091–102
  • Eisner A., Stoumbos V. D., Klein M. L., Fleming S. A. Relations between fundus appearance and function. Eyes whose fellow eye has exudative age‐related macular degeneration. Invest Ophthalmol Vis Sci 1991; 32: 8–20
  • Johnson P. T., Brown M. N., Pulliam B. C., Anderson D. H., Johnson L. V. Synaptic pathology, altered gene expression, and degeneration in photoreceptors impacted by drusen. Invest Ophthalmol Vis Sci 2005; 46: 4788–95
  • Johnson P. T., Lewis G. P., Talaga K. C., Brown M. N., Kappel P. J., Fisher S. K., et al. Drusen‐associated degeneration in the retina. Invest Ophthalmol Vis Sci 2003; 44: 4481–8
  • Hageman G. S., Luthert P. J., Victor Chong N. H., Johnson L. V., Anderson D. H., Mullins R. F. 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: 705–32
  • Anderson D., Mullins R., Hageman G., Johnson L. V. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002; 134: 411–31
  • Killingsworth M., Sarks J., Sarks S. Macrophages related to Bruch's membrane in age‐related macular degeneration. Eye 1990; 4: 613–21
  • Penfold P. L., Madigan M. C., Gillies M. C., Provis J. M. Immunological and Aetiological Aspects of Macular Degeneration. Progress in Retinal Research. Elsevier Science Ltd, London 2001; 385–414
  • Heriot W., Henkind P., Bellhorn R., Burns M. Choroidal neovascularization can digest Bruch's membrane. A prior break is not essential. Ophthalmology 1984; 91: 1603–8
  • Penfold P., Killingsworth M., Sarks S. An ultrastructural study of the role of leucocytes and fibroblasts in the breakdown of Bruch's membrane. Aust J Ophthalmol 1984; 12: 23–31
  • Dastgheib K., Green W. Granulomatous reaction to Bruch's membrane in age‐related macular degeneration. Arch Ophthalmol 1994; 112: 813–8
  • Hageman G., Mullins R., Russell S., Johnson L., Anderson D. Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J 1999; 13: 477–84
  • Mullins R. F., Russell S. R., Anderson D. H., Hageman G. S. 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
  • Johnson L., Ozaki S., Staples M., Erickson P., Anderson D. A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 2000; 70: 441–9
  • Johnson L., Leitner W., Staples M., Anderson D. Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 2001; 73: 887–96
  • Mullins R. F., Johnson L. V., Anderson D. H., Hageman G. S. Characterization of drusen‐associated glycoconjugates. Ophthalmology 1997; 104: 288–94
  • Russell S. R., Mullins R. F., Schneider B. L., Hageman G. S. Location, substructure, and composition of basal laminar drusen compared with drusen associated with aging and age‐related macular degeneration. Am J Ophthalmol 2000; 129: 205–14
  • Mullins R. F., Aptsiauri N., Hageman G. S. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye 2001; 15((Pt 3))390–5
  • Johnson L. V., Leitner W. P., Rivest A. J., Staples M. K., Radeke M. J., Anderson D. H. 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 U S A 2002; 99: 11830–5
  • Malek G., Li C. M., Guidry C., Medeiros N. E., Curcio C. A. Apolipoprotein B in cholesterol‐containing drusen and basal deposits of human eyes with age‐related maculopathy. Am J Pathol 2003; 162: 413–25
  • Anderson D., Talaga K., Rivest A., Barron E., Hageman G., Johnson L. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age‐related macular degeneration. Exp Eye Res 2004; 78: 243–56
  • Peto T., Lengyel I., Frederickson C., Vankuijk F. Zinc in Drusen. Invest Ophthalmol Vis Sci 2005; 46, E‐Abstract 3008
  • Holers V. M. The complement system as a therapeutic target in autoimmunity. Clin Immunol 2003; 107: 140–51
  • Fearon D. T., Locksley R. M. The instructive role of innate immunity in the acquired immune response. Science 1996; 272: 50–3
  • Mastellos D., Andronis C., Persidis A., Lambris J. D. Novel biological networks modulated by complement. Clin Immunol 2005; 115: 225–35
  • Mastellos D., Germenis A. E., Lambris J. D. Complement: an inflammatory pathway fulfilling multiple roles at the interface of innate immunity and development. Curr Drug Targets Inflamm Allergy 2005; 4): 125–7
  • Walport M. J. Complement. Second of two parts. N Engl J Med 2001; 344: 1140–4
  • Walport M. J. Complement. First of two parts. N Engl J Med 2001; 344: 1058–66
  • Thurman J. M., Holers V. M. The central role of the alternative complement pathway in human disease. J Immunol 2006; 176: 1305–10
  • Pio R., Martinez A., Unsworth E. J., Kowalak J. A., Bengoechea J. A., Zipfel P. F., et al. Complement factor H is a serum‐binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 2001; 276: 12292–300
  • Holers V. M., Thurman J. M. The alternative pathway of complement in disease: opportunities for therapeutic targeting. Mol Immunol 2004; 41: 147–52
  • Song W. C. Membrane complement regulatory proteins in autoimmune and inflammatory tissue injury. Curr Dir Autoimmun 2004; 7: 181–99
  • Zipfel P. F., Heinen S., Jozsi M., Skerka C. Complement and diseases: defective alternative pathway control results in kidney and eye diseases. Mol Immunol 2006; 43: 97–106
  • Halstensen T. S., Mollnes T. E., Fausa O., Brandtzaeg P. Deposits of terminal complement complex (TCC) in muscularis mucosae and submucosal vessels in ulcerative colitis and Crohn's disease of the colon. Gut 1989; 30: 361–6
  • Sospedra M., Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683–747
  • Lassmann H. Recent neuropathological findings in MS—implications for diagnosis and therapy. J Neurol 2004 Sep; 251(Suppl 4)IV2–5
  • Neumann E., Barnum S. R., Tarner I. H., Echols J., Fleck M., Judex M., et al. Local production of complement proteins in rheumatoid arthritis synovium. Arthritis Rheum 2002; 46: 934–45
  • Tang S., Lui S. L., Lai K. N. Pathogenesis of lupus nephritis: an update. Nephrology (Carlton) 2005; 10: 174–9
  • Turnberg D., Cook H. T. Complement and glomerulonephritis: new insights. Curr Opin Nephrol Hypertens 2005; 14: 223–8
  • Gerard N. P., Gerard C. Complement in allergy and asthma. Curr Opin Immunol 2002; 14: 705–8
  • Rodriguez de Cordoba S., Esparza‐Gordillo J., Goicoechea de Jorge E., Lopez‐Trascasa M., Sanchez‐Corral P. The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 2004; 41: 355–67
  • Pangburn M. K., Pangburn K. L., Koistinen V., Meri S., Sharma A. K. 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
  • Zipfel P. F. Complement factor H: physiology and pathophysiology. Semin Thromb Hemost 2001; 27: 191–9
  • Hageman G. S., Anderson D. H., Johnson L. V., Hancox L. S., Taiber A. J., Hardisty L. I., 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: 7227–32
  • Johnson L. V., Talaga K. C., Rivest A. J., Staples M. K., Radeke M. J., Barron E., et al. Characterization of Beta Amyloid‐Containing Vesicles within Drusen. Invest Ophthalmol Vis Sci 2003; 44, E‐Abstract 4229
  • Hageman G., Luthert P., Chong N., Johnson L., Anderson D., Mullins R. 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: 705–32
  • Miller D. M., Espinosa‐Heidmann D. G., Legra J., Dubovy S. R., Suner I. J., Sedmak D. D., et al. The association of prior cytomegalovirus infection with neovascular age‐related macular degeneration. Am J Ophthalmol 2004; 138: 323–8
  • Klein M., Mauldin W., Stoumbos V. Heredity and age‐related macular degeneration. Observations in monozygotic twins. Arch Ophthalmol 1994; 112: 932–7
  • Heiba I., Elston R., Klein B., Klein R. Sibling correlations and segregation analysis of age‐related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol 1994; 11: 51–67
  • Seddon J., Ajani U., Mitchell B. Familial aggregation of age‐related maculopathy. Am J Ophthalmol 1997; 123: 199–206
  • Meyers S. M., Greene T., Gutman F. A. A twin study of age‐related macular degeneration. Am J Ophthalmol 1995; 120: 757–66
  • Hammond C. J., Webster A. R., Snieder H., Bird A. C., Gilbert C. E., Spector T. D. Genetic influence on early age‐related maculopathy: a twin study. Ophthalmology 2002; 109: 730–6
  • Abecasis G. R., Yashar B. M., Zhao Y., Ghiasvand N. M., Zareparsi S., Branham K. E., et al. Age‐related macular degeneration: a high‐resolution genome scan for susceptibility loci in a population enriched for late‐stage disease. Am J Hum Genet 2004; 74: 482–94
  • Iyengar S. K., Song D., Klein B. E., Klein R., Schick J. H., Humphrey J., et al. Dissection of genomewide‐scan data in extended families reveals a major locus and oligogenic susceptibility for age‐related macular degeneration. Am J Hum Genet 2004; 74: 20–39
  • Klein M. L., Schultz D. W., Edwards A., Matise T. C., Rust K., Berselli C. B., et al. Age‐related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol 1998; 116: 1082–8
  • Majewski J., Schultz D. W., Weleber R. G., Schain M. B., Edwards A. O., Matise T. C., et al. Age‐related macular degeneration—a genome scan in extended families. Am J Hum Genet 2003; 73: 540–50
  • Schick J. H., Iyengar S. K., Klein B. E., Klein R., Reading K., Liptak R., et al. A whole‐genome screen of a quantitative trait of age‐related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet 2003; 72: 1412–24
  • Seddon J. M., Santangelo S. L., Book K., Chong S., Cote J. A genomewide scan for age‐related macular degeneration provides evidence for linkage to several chromosomal regions. Am J Hum Genet 2003; 73: 780–90
  • Weeks D. E., Conley Y. P., Mah T. S., Paul T. O., Morse L., Ngo‐Chang J., et al. A full genome scan for age‐related maculopathy. Hum Mol Genet 2000; 9: 1329–49
  • Weeks D. E., Conley Y. P., Tsai H. J., Mah T. S., Rosenfeld P. J., Paul T. O., et al. Age‐related maculopathy: an expanded genome‐wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. Am J Ophthalmol 2001; 132: 682–92
  • Weeks D. E., Conley Y. P., Tsai H. J., Mah T. S., Schmidt S., Postel E. A., et al. Age‐Related Maculopathy: A Genomewide Scan with Continued Evidence of Susceptibility Loci within the 1q31, 10q26, and 17q25 Regions. Am J Hum Genet 2004; 75((2))174–89
  • Fisher S. A., Abecasis G. R., Yashar B. M., Zareparsi S., Swaroop A., Iyengar S. K., et al. Meta‐analysis of genome scans of age‐related macular degeneration. Hum Mol Genet 2005; 14: 2257–64
  • Schultz D., Klein M., Humpert A., Luzier C., 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
  • Conley Y. P., Thalamuthu A., Jakobsdottir J., Weeks D. E., Mah T., Ferrell R. E., et al. Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age‐related maculopathy. Hum Mol Genet 2005; 14: 1991–2002
  • Haines J. L., Schnetz‐Boutaud N., Schmidt S., Scott W. K., Agarwal A., Postel E. A., 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
  • Stone E. M., Braun T. A., Russell S. R., Kuehn M. H., Lotery A. J., Moore P. A., et al. Missense variations in the fibulin 5 gene and age‐related macular degeneration. N Engl J Med 2004; 351: 346–53
  • Zareparsi S., Buraczynska M., Branham K. E., 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
  • Souied E. H., Benlian P., Amouyel P., Feingold J., Lagarde J. P., Munnich A., 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: 353–9
  • Klaver C. C., Kliffen M., van Duijn C. M., Hofman A., Cruts M., Grobbee D. E., et al. Genetic association of apolipoprotein E with age‐related macular degeneration. Am J Hum Genet 1998; 63: 200–6
  • Baird P. N., Guida E., Chu D. T., Vu H. T., Guymer R. H. The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age‐related macular degeneration. Invest Ophthalmol Vis Sci 2004; 45: 1311–5
  • Allikmets R., Shroyer N., Singh N., Seddon J., Lewis R., Bernstein P., et al. Mutation of the Stargardt disease gene (ABCR) in age‐related macular degeneration. Science 1997; 277: 1805–7
  • Klein R. J., Zeiss C., Chew E. Y., Tsai J. Y., Sackler R. S., Haynes C., et al. Complement factor H polymorphism in age‐related macular degeneration. Science 2005; 15(308)385–9
  • Edwards A. O., Ritter R., 3rd., Abel K. J., Manning A., Panhuysen C., Farrer L. A. Complement factor H polymorphism and age‐related macular degeneration. Science 2005; 308: 421–4
  • Haines J. L., Hauser M. A., Schmidt S., Scott W. K., Olson L. M., Gallins P., et al. Complement factor H variant increases the risk of age‐related macular degeneration. Science 2005; 308: 419–21
  • Zareparsi S., Branham K. E., Li M., Shah S., Klein R. J., Ott J., 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: 149–53
  • Magnusson K. P., Duan S., Sigurdsson H., Petursson H., Yang Z., Zhao Y., et al. CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. PLoS Med 2006; 3: e5
  • Sepp T., Khan J. C., Thurlby D. A., Shahid H., Clayton D. G., Moore A. T., et al. Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006; 47: 536–40
  • Souied E. H., Leveziel N., Richard F., Dragon‐Durey M. A., Coscas G., Soubrane G., et al. Y402H complement factor H polymorphism associated with exudative age‐related macular degeneration in the French population. Mol Vis 2005; 11: 1135–40
  • Okamoto H., Umeda S., Obazawa M., Minami M., Noda T., Mizota A., et al. Complement factor H polymorphisms in Japanese population with age‐related macular degeneration. Mol Vis 2006; 12: 156–8
  • Gold B., Merriam J. E., Zernant J., Hancox L. S., Taiber A. J., Gehrs K., et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age‐related macular degeneration. Nat Genet 2006; 38: 458–62
  • Lokki M. L., Koskimies S. A. Allelic differences in hemolytic activity and protein concentration of BF molecules are found in association with particular HLA haplotypes. Immunogenetics 1991; 34: 242–6
  • Jakobsdottir J., Conley Y. P., Weeks D. E., Mah T. S., Ferrell R. E., Gorin M. B. Susceptibility genes for age‐related maculopathy on chromosome 10q26. Am J Hum Genet 2005; 77: 389–407
  • Rivera A., Fisher S. A., Fritsche L. G., Keilhauer C. N., Lichtner P., Meitinger T., 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: 3227–36
  • Schmidt S., Hauser M. A., Scott W. K., Postel E. A., Agarwal A., Gallins P., et al. Cigarette smoking strongly modifies the association of LOC387715 and age‐related macular degeneration. Am J Hum Genet 2006; 78: 852–64
  • Saunders R. E., Goodship T. H., Zipfel P. F., Perkins S. J. An interactive web database of factor H‐associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease‐associated mutations. Hum Mutat 2006; 27: 21–30
  • Heinen S., Sanchez‐Corral P., Jackson M. S., Strain L., Goodship J. A., Kemp E. J., 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: 292–3
  • Warwicker P., Goodship T. H., Donne R. L., Pirson Y., Nicholls A., Ward R. M., et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 1998; 53: 836–44
  • Esparza‐Gordillo J., Goicoechea de Jorge E., Buil A., Carreras Berges L., Lopez‐Trascasa M., Sanchez‐Corral P., et al. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 2005; 14: 703–12
  • Caprioli J., Castelletti F., Bucchioni S., Bettinaglio P., Bresin E., Pianetti G., et al. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C‐257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet 2003; 12: 3385–95
  • Caprioli J., Noris M., Brioschi S., Pianetti G., Castelletti F., Bettinaglio P., et al. Genetics of HUS: the impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006; 108: 1267–79
  • Atkinson J. P., Liszewski M. K., Richards A., Kavanagh D., Moulton E. A. Hemolytic uremic syndrome: an example of insufficient complement regulation on self‐tissue. Ann N Y Acad Sci 2005; 1056: 144–52
  • Abrera‐Abeleda M. A., Nishimura C., Smith J. L., Sethi S., McRae J. L., Murphy B. F., 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: 582–9
  • Appel G. B., Cook H. T., Hageman G., Jennette J. C., Kashgarian M., Kirschfink M., et al. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 2005; 16: 1392–403
  • Robman L., Mahdi O., McCarty C., Dimitrov P., Tikellis G., McNeil J., et al. Exposure to Chlamydia pneumoniae infection and progression of age‐related macular degeneration. Am J Epidemiol 2005; 161: 1013–9
  • Erkkila H., Raitta C., Niemi K. Ocular findings in four siblings with pseudoxanthoma elasticum. Acta Ophthalmol (Copenh) 1983; 61: 589–99
  • Zee R. Y., Diehl K. A., Ridker P. M. Complement factor H Y402H gene polymorphism, C‐reactive protein, and risk of incident myocardial infarction, ischaemic stroke, and venous thromboembolism: A nested case‐control study. Atherosclerosis 2006; 187: 332–5

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