Skip to main content

Advertisement

Log in

Progress in defining the molecular biology of age related macular degeneration

  • Review
  • Published:
Human Genetics Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

References

  • Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KE, Reddick AC, Trager EH, Yoshida S, Bahling J, Filippova E, Elner S, Johnson MW, Vine AK, Sieving PA, Jacobson SG, Richards JE, Swaroop A (2004) Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 74:482–494

    Article  PubMed  CAS  Google Scholar 

  • Alexander JJ, Quigg RJ (2007) The simple design of complement factor H: looks can be deceiving. Mol Immunol 44:123–132

    Article  PubMed  CAS  Google Scholar 

  • Allikmets R (2000) Further evidence for an association of ABCR alleles with age-related macular degeneration. Am J Hum Genet 67:487–491

    Article  PubMed  CAS  Google Scholar 

  • Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M (1997a) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration (see comments). Science 277:1805–7

    Article  PubMed  CAS  Google Scholar 

  • Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR (1997b) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15:236–246

    Article  PubMed  CAS  Google Scholar 

  • Allikmets R, Seddon JM, Bernstein PS, Hutchinson A, Atkinson A, Sharma S, Gerrard B, Li W, Metzker ML, Wadelius C, Caskey CT, Dean M, Petrukhin K (1999) Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies. Hum Genet 104:449–53

    Article  PubMed  CAS  Google Scholar 

  • Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 9:1390–1397

    Article  PubMed  CAS  Google Scholar 

  • Anderson DH, Mullins RF, Hageman GS, Johnson LV (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134:411–431

    Article  PubMed  CAS  Google Scholar 

  • Anderson DH, Talaga KC, Rivest AJ, Barron E, Hageman GS, Johnson LV (2004) Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res 78:243–256

    Article  PubMed  CAS  Google Scholar 

  • Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Wurzner R, Zipfel PF (2005) Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 16:1392–1403

    Article  PubMed  Google Scholar 

  • AREDS (2000) Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology 107:2224–2232

    Article  Google Scholar 

  • AREDS (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 119:1417–1436

    Google Scholar 

  • Augood CA, Vingerling JR, de Jong PT, Chakravarthy U, Seland J, Soubrane G, Tomazzoli L, Topouzis F, Bentham G, Rahu M, Vioque J, Young IS, Fletcher AE (2006) Prevalence of age-related maculopathy in older Europeans: The European Eye Study (EUREYE). Arch Ophthalmol 124:529–535

    Article  PubMed  Google Scholar 

  • Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ (2006) Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 113:363–372

    Article  PubMed  Google Scholar 

  • Ayyagari R, Zhang K, Hutchinson A, Yu Z, Swaroop A, Kakuk LE, Seddon JM, Bernstein PS, Lewis RA, Tammur J, Yang Z, Li Y, Zhang H, Yashar BM, Liu J, Petrukhin K, Sieving PA, Allikmets R (2001) Evaluation of the ELOVL4 gene in patients with age-related macular degeneration. Ophthalmic Genet 22:233–239

    Article  PubMed  CAS  Google Scholar 

  • Baird PN, Chu D, Guida E, Vu HT, Guymer R (2004a) Association of the M55L and Q192R paraoxonase gene polymorphisms with age-related macular degeneration. Am J Ophthalmol 138:665–666

    Article  PubMed  CAS  Google Scholar 

  • Baird PN, Guida E, Chu DT, Vu HT, Guymer RH (2004b) The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 45:1311–1315

    Article  PubMed  Google Scholar 

  • Behndig A, Svensson B, Marklund SL, Karlsson K (1998) Superoxide dismutase isoenzymes in the human eye. Invest Ophthalmol Vis Sci 39:471–475

    PubMed  CAS  Google Scholar 

  • Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, de Jong PT, Klaver CC, Klein BE, Klein R (1995) An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 39:367–374

    Article  PubMed  CAS  Google Scholar 

  • Blacharski PA (1988) Fundus flavimaculatus. In: Newsome DA (ed) Retinal dystrophies and degenerations. Raven Press, New York, pp 135–159

    Google Scholar 

  • Blackmore TK, Sadlon TA, Ward HM, Lublin DM, Gordon DL (1996) Identification of a heparin binding domain in the seventh short consensus repeat of complement factor H. J Immunol 157:5422–5427

    PubMed  CAS  Google Scholar 

  • Blackmore TK, Fischetti VA, Sadlon TA, Ward HM, Gordon DL (1998) M protein of the group A Streptococcus binds to the seventh short consensus repeat of human complement factor H. Infect Immun 66:1427–1431

    PubMed  CAS  Google Scholar 

  • Bonastre J, Le PC, Anderson P, Ganz A, Berto P, Berdeaux G (2002) The epidemiology, economics and quality of life burden of age-related macular degeneration in France, Germany, Italy and the United Kingdom. Eur J Health Econ 3:94–102

    Article  PubMed  CAS  Google Scholar 

  • Brera-Abeleda MA, Nishimura C, Smith JLH, Sethi S, McRae JL, Murphy BF, Silvestri G, Skerka C, Jozsi M, Zipfel PF, Hageman GS, Smith RJH (2006) 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 43:582–589

    Article  CAS  Google Scholar 

  • Brody BL, Gamst AC, Williams RA, Smith AR, Lau PW, Dolnak D, Rapaport MH, Kaplan RM, Brown SI (2001) Depression, visual acuity, comorbidity, and disability associated with age-related macular degeneration. Ophthalmology 108:1893–1900

    Article  PubMed  CAS  Google Scholar 

  • Brown MM, Brown GC, Stein JD, Roth Z, Campanella J, Beauchamp GR (2005) Age-related macular degeneration: economic burden and value-based medicine analysis. Can J Ophthalmol 40:277–287

    PubMed  Google Scholar 

  • Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432–1444

    Article  PubMed  CAS  Google Scholar 

  • Cameron DJ, Yang Z, Gibbs D, Chen H, Kaminoh Y, Jorgensen A, Zeng J, Luo L, Brinton E, Brinton G, Brand JM, Bernstein PS, Zabriskie NA, Tang S, Constantine R, Tong Z, Zhang K (2007) HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration. Cell Cycle 6:1122–1125

    PubMed  CAS  Google Scholar 

  • Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    Article  PubMed  CAS  Google Scholar 

  • Carreno MP, Labarre D, Maillet F, Jozefowicz M, Kazatchkine MD (1989) Regulation of the human alternative complement pathway: formation of a ternary complex between factor H, surface-bound C3b and chemical groups on nonactivating surfaces. Eur J Immunol 19:2145–2150

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Miyamura N, Ninomiya Y, Handa JT (2003) Distribution of the collagen IV isoforms in human Bruch’s membrane. Br J Ophthalmol 87:212–215

    Article  PubMed  CAS  Google Scholar 

  • 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 73:209–218

    PubMed  CAS  Google Scholar 

  • Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE (1996) A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 276:1147–1151

    Article  PubMed  CAS  Google Scholar 

  • Churchill AJ, Carter JG, Lovell HC, Ramsden C, Turner SJ, Yeung A, Escardo J, Atan D (2006) VEGF polymorphisms are associated with neovascular age-related macular degeneration. Hum Mol Genet 15:2955–2961

    Article  PubMed  CAS  Google Scholar 

  • 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 281:24713–24720

    Article  PubMed  CAS  Google Scholar 

  • Conley YP, Thalamuthu A, Jakobsdottir J, Weeks DE, Mah T, Ferrell RE, Gorin MB (2005) 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 14:1991–2002

    Article  PubMed  CAS  Google Scholar 

  • Cruickshanks KJ, Hamman RF, Klein R, Nondahl DM, Shetterly SM (1997) The prevalence of age-related maculopathy by geographic region and ethnicity. The Colorado–Wisconsin study of age-related maculopathy. Arch Ophthalmol 115:242–250

    PubMed  CAS  Google Scholar 

  • Cunha-Vaz JG (1976) The blood-retinal barriers. Doc Ophthalmol 41:287–327

    Article  PubMed  CAS  Google Scholar 

  • Darzins P, Mitchell P, Heller RF (1997) Sun exposure and age-related macular degeneration. An Australian case-control study. Ophthalmology 104:770–776

    PubMed  CAS  Google Scholar 

  • 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 125:49–54

    Article  PubMed  CAS  Google Scholar 

  • De La Paz MA, Guy VK, Abou-Donia S, Heinis R, Bracken B, Vance JM, Gilbert JR, Gass JD, Haines JL, Pericak-Vance MA (1999) Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration. Ophthalmology 106:1531–1536

    Article  PubMed  Google Scholar 

  • Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, Vernet MH (2001) Associations of cardiovascular disease and its risk factors with age-related macular degeneration: The POLA Study. Ophthalmic Epidemiol 8:237–249

    Article  PubMed  CAS  Google Scholar 

  • 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 296:301–309

    Article  PubMed  Google Scholar 

  • DeWan A, Liu M, Hartman S, Zhang S, Liu DTL, Zhao C, Tam POS, Chan WM, Lam DSC, Snyder M, Barnstable C, Pang CP, Hoh J (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314(5801):989–992

    Article  PubMed  CAS  Google Scholar 

  • Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman FW, Weiss L (2004) Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 15:787–795

    Article  PubMed  CAS  Google Scholar 

  • Dryja TP, Briggs CE, Berson EL, Rosenfeld PJ, Abitbol M, Klaver CC, Assink JJ, Bergen AA, van D, Dean M, Allikmets R, Shroyer NF, Lupski JR, Lewis RA, Leppert M, Bernstein PS, Johanna M (1998) ABCR gene and age-related macular degeneration. Science 279:1107a

  • 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 73:900–906

    Article  PubMed  CAS  Google Scholar 

  • Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424

    Article  PubMed  CAS  Google Scholar 

  • Ennis S, Goverdhan S, Cree AJ, Hoh J, Collins A, Lotery AJ (2007) Fine scale linkage disequilibrium mapping of age related macular degeneration in the complement factor H gene region. Br J Ophthalmol 91(7):966-970

    Article  PubMed  Google Scholar 

  • Esfandiary H, Chakravarthy U, Patterson C, Young I, Hughes AE (2005) Association study of detoxification genes in age related macular degeneration. Br J Ophthalmol 89:470–474

    Article  PubMed  CAS  Google Scholar 

  • Evans JR (2001) Risk factors for age-related macular degeneration. Prog Retin Eye Res 20:227–253

    Article  PubMed  CAS  Google Scholar 

  • Feeney-Burns L, Ellersieck MR (1985) Age-related changes in the ultrastructure of Bruch’s membrane. Am J Ophthalmol 100:686–697

    PubMed  CAS  Google Scholar 

  • Ferrara N (2002) Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 29:10–14

    PubMed  CAS  Google Scholar 

  • Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851–858

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  PubMed  CAS  Google Scholar 

  • Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, Milton RC, Bressler SB, Klein R (2005) A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 123:1570–1574

    Article  PubMed  Google Scholar 

  • Fiotti N, Pedio M, Battaglia PM, Altamura N, Uxa L, Guarnieri G, Giansante C, Ravalico G (2005) MMP-9 microsatellite polymorphism and susceptibility to exudative form of age-related macular degeneration. Genet Med 7:272–277

    Article  PubMed  CAS  Google Scholar 

  • Friedman DS, Katz J, Bressler NM, Rahmani B, Tielsch JM (1999) Racial differences in the prevalence of age-related macular degeneration: the Baltimore Eye Survey. Ophthalmology 106:1049–1055

    Article  PubMed  CAS  Google Scholar 

  • Friedman DS, O’Colmain BJ, Munoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P, Kempen J (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122:564–572

    Article  PubMed  Google Scholar 

  • Gehrs K, Anderson D, Johnson L, Hageman G (2006) Age related macular degeneration—emerging pathogenetic and therapeutic concepts. Ann Med 38:450–471

    Article  PubMed  Google Scholar 

  • Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, Hageman GS, Dean M, Allikmets R, Chang S, Yannuzzi LA, Merriam JC, Barbazetto I, Lerner LE, Russell S, Hoballah J, Hageman J, Stockman H (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38:458–462

    Article  PubMed  CAS  Google Scholar 

  • Gotoh N, Kuroiwa S, Kikuchi T, Arai J, Arai S, Yoshida N, Yoshimura N (2004) Apolipoprotein E polymorphisms in Japanese patients with polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Am J Ophthalmol 138:567–573

    Article  PubMed  CAS  Google Scholar 

  • Gotoh N, Yamada R, Hiratani H, Renault V, Kuroiwa S, Monet M, Toyoda S, Chida S, Mandai M, Otani A, Yoshimura N, Matsuda F (2006) No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum Genet 120:139–143

    Article  PubMed  CAS  Google Scholar 

  • Gottfredsdottir MS, Sverrisson T, Musch DC, Stefansson E (1999) Age related macular degeneration in monozygotic twins and their spouses in Iceland. Acta Ophthalmol Scand 77:422–425

    Article  PubMed  CAS  Google Scholar 

  • Goverdhan SV, Howell MW, Mullins RF, Osmond C, Hodgkins PR, Self J, Avery K, Lotery AJ (2005) Association of HLA class I and class II polymorphisms with age-related macular degeneration. Invest Ophthalmol Vis Sci 46:1726–1734

    Article  PubMed  Google Scholar 

  • Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR (2004) Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805–2816

    Article  PubMed  CAS  Google Scholar 

  • Grassi MA, Fingert JH, Scheetz TE, Roos BR, Ritch R, West SK, Kawase K, Shire AM, Mullins RF, Stone EM (2006) Ethnic variation in AMD-associated complement factor H polymorphism p.Tyr402His. Hum Mutat 27:921–925

    Article  PubMed  CAS  Google Scholar 

  • Gregor Z, Joffe L (1978) Senile macular changes in the black African. Br J Ophthalmol 62:547–550

    Article  PubMed  CAS  Google Scholar 

  • Guymer RH, Heon E, Lotery AJ, Munier FL, Schorderet DF, Baird PN, McNeil RJ, Haines H, Sheffield VC, Stone EM (2001) Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch Ophthalmol 119:745–751

    PubMed  CAS  Google Scholar 

  • Guymer RH, Chiu AW, Lim L, Baird PN (2005) HMG CoA reductase inhibitors (statins): do they have a role in age-related macular degeneration? Surv Ophthalmol 50:194–206

    Article  PubMed  Google Scholar 

  • Haab O (1885) Erkrankungen der Macula Lutea. Zentralbl Augenheilkd 9:384–391

    Google Scholar 

  • Hageman GS, Mullins RF, Russell SR, Johnson LV, Anderson DH (1999) Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J 13:477–484

    PubMed  CAS  Google Scholar 

  • Hageman GS, Luthert PJ, Victor Chong NH, 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 aging and age-related macular degeneration. Prog Retin Eye Res 20:705–732

    Article  PubMed  CAS  Google Scholar 

  • 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) From The cover: a common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102:7227–7232

    Article  PubMed  CAS  Google Scholar 

  • 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 308:419–421

    Article  PubMed  CAS  Google Scholar 

  • Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agarwal A, Postel EA, Olson L, Kenealy SJ, Hauser M, Gilbert JR, Pericak-Vance MA (2006) Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci 47:329–335

    Article  PubMed  Google Scholar 

  • Hall NF, Gale CR, Syddall H, Phillips DI, Martyn CN (2001) Risk of macular degeneration in users of statins: cross sectional study. BMJ 323:375–376

    Article  PubMed  CAS  Google Scholar 

  • Hamdi HK, Reznik J, Castellon R, Atilano SR, Ong JM, Udar N, Tavis JH, Aoki AM, Nesburn AB, Boyer DS, Small KW, Brown DJ, Kenney MC (2002) Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration. Biochem Biophys Res Commun 295:668–672

    Article  PubMed  CAS  Google Scholar 

  • Hammond CJ, Webster AR, Snieder H, Bird AC, Gilbert CE, Spector TD (2002) Genetic influence on early age-related maculopathy: a twin study. Ophthalmology 109:730–736

    Article  PubMed  Google Scholar 

  • Hayashi M, Merriam JE, Klaver CC, Zernant J, Bergen AA, Smith RT, Chang S, Merriam JC, Allikmets R (2004) Evaluation of the ARMD1 locus on 1q25–31 in patients with age-related maculopathy: genetic variation in laminin genes and in exon 104 of HEMICENTIN-1. Ophthalmic Genet 25:111–119

    Article  PubMed  CAS  Google Scholar 

  • Heiba IM, Elston RC, Klein BE, Klein R (1994) Sibling correlations and segregation analysis of age-related maculopathy: The Beaver Dam Eye Study. Genet Epidemiol 11:51–67

    Article  PubMed  CAS  Google Scholar 

  • Herbert AP, Uhrin D, Lyon M, Pangburn MK, Barlow PN (2006) Disease-associated sequence variations congregate in a polyanion recognition patch on human factor H revealed in three-dimensional structure. J Biol Chem 281:16512–16520

    Article  PubMed  CAS  Google Scholar 

  • Holers VM (2003) The complement system as a therapeutic target in autoimmunity. Clin Immunol 107:140–151

    Article  PubMed  CAS  Google Scholar 

  • Hughes AE, Orr N, Esfandiary H, az-Torres M, Goodship T, Chakravarthy U (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 38:1173–1177

    Article  PubMed  CAS  Google Scholar 

  • Hyman L, Neborsky R (2002) Risk factors for age-related macular degeneration: an update. Curr Opin Ophthalmol 13:171–175

    Article  PubMed  Google Scholar 

  • Ikeda T, Obayashi H, Hasegawa G, Nakamura N, Yoshikawa T, Imamura Y, Koizumi K, Kinoshita S (2001) Paraoxonase gene polymorphisms and plasma oxidized low-density lipoprotein level as possible risk factors for exudative age-related macular degeneration. Am J Ophthalmol 132:191–195

    Article  PubMed  CAS  Google Scholar 

  • Imamura Y, Noda S, Hashizume K, Shinoda K, Yamaguchi M, Uchiyama S, Shimizu T, Mizushima Y, Shirasawa T, Tsubota K (2006) Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. PNAS 103:11282–11287

    Article  PubMed  CAS  Google Scholar 

  • Iyengar SK, Song D, Klein BE, Klein R, Schick JH, Humphrey J, Millard C, Liptak R, Russo K, Jun G, Lee KE, Fijal B, Elston RC (2004) Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am J Hum Genet 74:20–39

    Article  PubMed  CAS  Google Scholar 

  • Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB (2005) Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 77:389–407

    Article  PubMed  CAS  Google Scholar 

  • Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH (2000) A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 70:441–449

    Article  PubMed  CAS  Google Scholar 

  • 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 73:887–896

    Article  PubMed  CAS  Google Scholar 

  • Jokiranta TS, Cheng ZZ, Seeberger H, Jozsi M, Heinen S, Noris M, Remuzzi G, Ormsby R, Gordon DL, Meri S, Hellwage J, Zipfel PF (2005) Binding of complement factor H to endothelial cells is mediated by the carboxy-terminal glycosaminoglycan binding site. Am J Pathol 167:1173–1181

    PubMed  CAS  Google Scholar 

  • Karkkainen MJ, Makinen T, Alitalo K (2002) Lymphatic endothelium: a new frontier of metastasis research. Nat Cell Biol 4:E2–E5

    Article  PubMed  CAS  Google Scholar 

  • Keyt BA, Berleau LT, Nguyen HV, Chen H, Heinsohn H, Vandlen R, Ferrara N (1996) The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency. J Biol Chem 271:7788–7795

    Article  PubMed  CAS  Google Scholar 

  • Khan JC, Shahid H, Thurlby DA, Bradley M, Clayton DG, Moore AT, Bird AC, Yates JR (2006a) Age related macular degeneration and sun exposure, iris colour, and skin sensitivity to sunlight. Br J Ophthalmol 90:29–32

    Article  PubMed  CAS  Google Scholar 

  • Khan JC, Thurlby DA, Shahid H, Clayton DG, Yates JR, Bradley M, Moore AT, Bird AC (2006b) Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol 90:75–80

    Article  PubMed  CAS  Google Scholar 

  • Kimura K, Isashiki Y, Sonoda S, Kakiuchi-Matsumoto T, Ohba N (2000) Genetic association of manganese superoxide dismutase with exudative age-related macular degeneration. Am J Ophthalmol 130:769–773

    Article  PubMed  CAS  Google Scholar 

  • Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, de Jong PT (1998a) Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 63:200–206

    Article  PubMed  CAS  Google Scholar 

  • Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT (1998b) Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol 116:1646–1651

    PubMed  CAS  Google Scholar 

  • Klaver CCW, Assink JJM, van Leeuwen R, Wolfs RCW, Vingerling JR, Stijnen T, Hofman A, de Jong PTVM (2001) Incidence and progression rates of age-related maculopathy: The Rotterdam Study. Invest Ophthalmol Vis Sci 42:2237–2241

    PubMed  CAS  Google Scholar 

  • Klein ML, Mauldin WM, Stoumbos VD (1994) Heredity and age-related macular degeneration. Observations in monozygotic twins. Arch Ophthalmol 112:932–937

    PubMed  CAS  Google Scholar 

  • Klein R, Klein BE, Jensen SC (1997) The relation of cardiovascular disease and its risk factors to the 5-year incidence of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology 104:1804–1812

    PubMed  CAS  Google Scholar 

  • Klein ML, Schultz DW, Edwards A, Matise TC, Rust K, Berselli CB, Trzupek K, Weleber RG, Ott J, Wirtz MK, Acott TS (1998) Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol 116:1082–8

    PubMed  CAS  Google Scholar 

  • Klein R, Klein BE, Jensen SC, Mares-Perlman JA, Cruickshanks KJ, Palta M (1999) Age-related maculopathy in a multiracial United States population: The National Health and Nutrition Examination Survey III. Ophthalmology 106:1056–1065

    Article  PubMed  CAS  Google Scholar 

  • Klein R, Klein BE, Marino EK, Kuller LH, Furberg C, Burke GL, Hubbard LD (2003a) Early age-related maculopathy in the cardiovascular health study. Ophthalmology 110:25–33

    Article  PubMed  Google Scholar 

  • Klein R, Klein BE, Tomany SC, Cruickshanks KJ (2003b) The association of cardiovascular disease with the long-term incidence of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology 110:1273–1280

    Article  PubMed  Google Scholar 

  • Klein R, Klein BE, Tomany SC, Danforth LG, Cruickshanks KJ (2003c) Relation of statin use to the 5-year incidence and progression of age-related maculopathy. Arch Ophthalmol 121:1151–1155

    Article  PubMed  CAS  Google Scholar 

  • 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 308:385–389

    Article  PubMed  CAS  Google Scholar 

  • Kolb H (2003) How the Retina Works. American Scientist 91:28–35

    Google Scholar 

  • Lau LI, Chen SJ, Cheng CY, Yen MY, Lee FL, Lin MW, Hsu WM, Wei YH (2006) Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest Ophthalmol Vis Sci 47:3242–3246

    Article  PubMed  Google Scholar 

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    Article  PubMed  CAS  Google Scholar 

  • Leys A, Vanrenterghem Y, Van Damme B, Snyers B, Pirson Y, Leys M (1991) Fundus changes in membranoproliferative glomerulonephritis type II. A fluorescein angiographic study of 23 patients Graefes Arch Clin Exp Ophthalmol 229:406–410

    Article  PubMed  CAS  Google Scholar 

  • Lotery AJ, Munier FL, Fishman GA, Weleber RG, Jacobson SG, Affatigato LM, Nichols BE, Schorderet DF, Sheffield VC, Stone EM (2000) Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. Invest Ophthalmol Vis Sci 41:1291–1296

    PubMed  CAS  Google Scholar 

  • Macular Photocoagulation Study Group (1997) Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Macular Photocoagulation Study Group Arch Ophthalmol 115:741–747

    Google Scholar 

  • Majewski J, Schultz DW, Weleber RG, Schain MB, Edwards AO, Matise TC, Acott TS, Ott J, Klein ML (2003) Age-related macular degeneration—a genome scan in extended families. Am J Hum Genet 73:540–550

    Article  PubMed  CAS  Google Scholar 

  • Malek G, Johnson LV, Mace BE, Saloupis P, Schmechel DE, Rickman DW, Toth CA, Sullivan PM, Bowes Rickman C (2005) Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. PNAS 102:11900–11905

    Article  PubMed  CAS  Google Scholar 

  • Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, Seddon JM (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 38:1055–1059

    Article  PubMed  CAS  Google Scholar 

  • Mandal MN, Ayyagari R (2006) Complement factor H: spatial and temporal expression and localization in the eye. Invest Ophthalmol Vis Sci 47:4091–4097

    Article  PubMed  Google Scholar 

  • Mares-Perlman JA, Brady WE, Klein R, VandenLangenberg GM, Klein BE, Palta M (1995) Dietary fat and age-related maculopathy. Arch Ophthalmol 113:743–748

    PubMed  CAS  Google Scholar 

  • Marmorstein L (2004) Association of EFEMP1 with malattia leventinese and age-related macular degeneration: a mini-review. Ophthalmic Genet 25:219–226

    Article  PubMed  CAS  Google Scholar 

  • McCarty CA, Mukesh BN, Guymer RH, Baird PN, Taylor HR (2001) Cholesterol-lowering medications reduce the risk of age-related maculopathy progression. Med J Aust 175:340

    PubMed  CAS  Google Scholar 

  • McGwin G Jr, Owsley C, Curcio CA, Crain RJ (2003) The association between statin use and age related maculopathy. Br J Ophthalmol 87:1121–1125

    Article  PubMed  Google Scholar 

  • McKay GJ, Clarke S, Hughes A, McConnell V, Schultz DW, Klein ML, Silvestri G, Simpson DA (2004) A novel diagnostic test detects a low frequency of the hemicentin Gln5345Arg variant among Northern Irish age related macular degeneration patients. Mol Vis 10:682–687

    PubMed  CAS  Google Scholar 

  • McLaughlin BJ, Fan W, Zheng JJ, Cai H, Del Priore LV, Bora NS, Kaplan HJ (2003) Novel role for a complement regulatory protein (CD46) in retinal pigment epithelial adhesion. Invest Ophthalmol Vis Sci 44:3669–3674

    Article  PubMed  Google Scholar 

  • Meyers SM, Zachary AA (1988) Monozygotic twins with age-related macular degeneration. Arch Ophthalmol 106:651–653

    PubMed  CAS  Google Scholar 

  • Meyers SM, Greene T, Gutman FA (1995) A twin study of age-related macular degeneration. Am J Ophthalmol 120:757–766

    PubMed  CAS  Google Scholar 

  • Mitchell P, Smith W, Attebo K, Wang JJ (1995) Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 102:1450–1460

    PubMed  CAS  Google Scholar 

  • Moss, Maass A, Lundh P, Cordeiro MF, Fitzke F, Pickering MC, Coffey P, Luthert PJ, Greenwood J (2006) In-vivo retinal imaging and anatomical findings in aged animals lacking the gene for complement factor-H. ARVO 2006 edn

  • Mullins RF, Johnson LV, Anderson DH, Hageman GS (1997) Characterization of drusen-associated glycoconjugates. Ophthalmology 104:288–94

    PubMed  CAS  Google Scholar 

  • Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) 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 14:835–846

    PubMed  CAS  Google Scholar 

  • 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 15:390–395

    PubMed  CAS  Google Scholar 

  • Munoz B, West SK, Rubin GS, Schein OD, Quigley HA, Bressler SB, Bandeen-Roche K (2000) Causes of blindness and visual impairment in a population of older Americans: The Salisbury Eye Evaluation Study. Arch Ophthalmol 118:819–825

    PubMed  CAS  Google Scholar 

  • Nettleship E (1884) Central senile areolar choroidal dystrophy. Trans Am Ophthalmol Soc 6:165–168

    Google Scholar 

  • Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, Chen Y, Zhang K, Ambati BK, Baffi JZ, Ambati J (2006) Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA 103:2328–2333

    Article  PubMed  CAS  Google Scholar 

  • Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, Tsuchiya A, Ueta Y, Soma A, Kanda H, Matsumoto M, Kawaichi M (2004) HtrA1 serine protease inhibits signaling mediated by Tgf{beta} family proteins. Development 131:1041–1053

    Article  PubMed  CAS  Google Scholar 

  • Oshima Y, Ishibashi T, Murata T, Tahara Y, Kiyohara Y, Kubota T (2001) Prevalence of age related maculopathy in a representative Japanese population: The Hisayama study. Br J Ophthalmol 85:1153–1157

    Article  PubMed  CAS  Google Scholar 

  • Pang CP, Baum L, Chan WM, Lau TC, Poon PM, Lam DS (2000) The apolipoprotein E epsilon4 allele is unlikely to be a major risk factor of age-related macular degeneration in Chinese. Ophthalmologica 214:289–291

    Article  PubMed  CAS  Google Scholar 

  • Pangburn MK, Pangburn KL, Koistinen V, Meri S, Sharma AK (2000) 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 164:4742–4751

    PubMed  CAS  Google Scholar 

  • Penfold P, Killingsworth M, Sarks S (1984) An ultrastructural study of the role of leucocytes and fibroblasts in the breakdown of Bruch’s membrane. Aust J Ophthalmol 12:23–31

    Article  PubMed  CAS  Google Scholar 

  • Penfold PL, Madigan MC, Gillies MC, Provis JM (2001) Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 20:385–414

    Article  PubMed  CAS  Google Scholar 

  • Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428

    PubMed  CAS  Google Scholar 

  • Pieramici DJ, Bressler NM, Bressler SB, Schachat AP (1994) Choroidal neovascularization in black patients. Arch Ophthalmol 112:1043–1046

    PubMed  CAS  Google Scholar 

  • Ram S, Sharma AK, Simpson SD, Gulati S, McQuillen DP, Pangburn MK, Rice PA (1998) A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae. J Exp Med 187:743–752

    Article  PubMed  CAS  Google Scholar 

  • Rivera A, White K, Stohr H, Steiner K, Hemmrich N, Grimm T, Jurklies B, Lorenz B, Scholl HP, Apfelstedt-Sylla E, Weber BH (2000) A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet 67:800–13

    Article  PubMed  CAS  Google Scholar 

  • Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, Weber BH (2005) 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 14:3227–3236

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez de CS, Esparza-Gordillo J, Goicoechea de JE, Lopez-Trascasa M, Sanchez-Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41:355–367

    Article  CAS  Google Scholar 

  • Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331–335

    PubMed  Google Scholar 

  • Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431

    Article  PubMed  CAS  Google Scholar 

  • Rovner BW, Casten RJ, Tasman WS (2002) Effect of depression on vision function in age-related macular degeneration. Arch Ophthalmol 120:1041–1044

    PubMed  Google Scholar 

  • Royal College of Ophthalmologists (2002) A national research strategy for ophthalmology. Royal College of Ophthalmologists

  • Russell SR, Mullins RF, Schneider BL, Hageman GS (2000) Location, substructure, and composition of basal laminar drusen compared with drusen associated with aging and age-related macular degeneration. Am J Ophthalmol 129:205–214

    Article  PubMed  CAS  Google Scholar 

  • Sastry BV, Hemontolor ME (1998) Influence of nicotine and cotinine on retinal phospholipase A2 and its significance to macular function. J Ocul Pharmacol Ther 14:447–458

    Article  PubMed  CAS  Google Scholar 

  • 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 125:55–62

    Article  PubMed  CAS  Google Scholar 

  • Schmidt S, Haines JL, Postel EA, Agarwal A, Kwan SY, Gilbert JR, Pericak-Vance MA, Scott WK (2005) Joint effects of smoking history and APOE genotypes in age-related macular degeneration. Mol Vis 11:941–949

    PubMed  CAS  Google Scholar 

  • Schmidt S, Hauser MA, Scott WK, Postel EA, Agarwal A, Gallins P, Wong F, Chen YS, Spencer K, Schnetz-Boutaud N, Haines JL, Pericak-Vance MA (2006) Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 78:852–864

    Article  PubMed  CAS  Google Scholar 

  • Schmidt S, Klaver CCW, Saunders AM, Postel EA, De La Paz MA, Agarwal A, Small KW, Udar N, Ong JM, Chalukya MV, Nesburn A, Cristina Kenney M, Domurath RM, Hogan M, Mah TS, Conley YP, Ferrell RE, Weeks DE, de Jong PTVM, van Duijn CM, Haines JL, Pericak-Vance MA, Gorin MB (2002) A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 23:209–223

    Article  PubMed  Google Scholar 

  • Schultz DW, Klein ML, Humpert A, Majewski J, Schain M, Weleber RG, Ott J, Acott TS (2003a) Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch Ophthalmol 121:679–683

    Article  PubMed  CAS  Google Scholar 

  • Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, Mahan A, Runckel C, Cassera M, Vittal V, Doyle TM, Martin TM, Weleber RG, Francis PJ, Acott TS (2003b) 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 12:3315–3323

    Article  PubMed  CAS  Google Scholar 

  • Seddon JM, Chen CA (2004) The epidemiology of age-related macular degeneration. Int Ophthalmol Clin 44:17–39

    Article  PubMed  Google Scholar 

  • Seddon JM, Ajani UA, Sperduto RD et al (1994) Dietary fat intake and age-related macular degeneration. Invest Ophthalmol Vis Sci 35:2003

    Google Scholar 

  • Seddon JM, Willett WC, Speizer FE, Hankinson SE (1996) A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 276:1141–1146

    Article  PubMed  CAS  Google Scholar 

  • Seddon JM, Rosner B, Sperduto RD, Yannuzzi L, Haller JA, Blair NP, Willett W (2001) Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol 119:1191–1199

    PubMed  CAS  Google Scholar 

  • Seddon JM, Cote J, Davis N, Rosner B (2003a) Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol 121:785–792

    Article  PubMed  Google Scholar 

  • Seddon JM, Santangelo SL, Book K, Chong S, Cote J (2003b) A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. Am J Hum Genet 73:780–790

    Article  PubMed  CAS  Google Scholar 

  • 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 123:321–327

    Article  PubMed  Google Scholar 

  • Seddon JM, George S, Rosner B (2006a) Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: The US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol 124:995–1001

    Article  PubMed  CAS  Google Scholar 

  • Seddon JM, George S, Rosner B, Klein ML (2006b) CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 61:157–165

    Article  PubMed  CAS  Google Scholar 

  • Seitsonen S, Lemmela S, Holopainen J, Tommila P, Ranta P, Kotamies A, Moilanen J, Palosaari T, Kaarniranta K, Meri S, Immonen I, Jarvela I (2006) Analysis of variants in the complement factor H, the elongation of very long chain fatty acids-like 4 and the hemicentin 1 genes of age-related macular degeneration in the Finnish population. Mol Vis 12:796–801

    PubMed  CAS  Google Scholar 

  • Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985

    Article  PubMed  CAS  Google Scholar 

  • 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 47:536–540

    Article  PubMed  Google Scholar 

  • Sharma AK, Pangburn MK (1996) Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis. Proc Natl Acad Sci USA 93:10996–11001

    Article  PubMed  CAS  Google Scholar 

  • Sharma AK, Pangburn MK (1997) Localization by site-directed mutagenesis of the site in human complement factor H that binds to Streptococcus pyogenes M protein. Infect Immun 65:484–487

    PubMed  CAS  Google Scholar 

  • Shiose Y, Oguri M (1969) Electron microscopic studies on the blood-retinal barrier and the blood-aqueous barrier. Nippon Ganka Gakkai Zasshi 73:1606–1622

    PubMed  CAS  Google Scholar 

  • Simonelli F, Margaglione M, Testa F, Cappucci G, Manitto MP, Brancato R, Rinaldi E (2001) Apolipoprotein E polymorphisms in age-related macular degeneration in an Italian population. Ophthalmic Res 33:325–328

    Article  PubMed  CAS  Google Scholar 

  • Simonelli F, Frisso G, Testa F, di Fiore R, Vitale DF, Manitto MP, Brancato R, Rinaldi E, Sacchetti L (2006) Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population. Br J Ophthalmol 90:1142–1145

    Article  PubMed  CAS  Google Scholar 

  • Smith JD, Miyata M, Poulin SE, Neveux LM, Craig WY (1998) The relationship between apolipoprotein E and serum oxidation-related variables is apolipoprotein E phenotype dependent. Int J Clin Lab Res 28:116–121

    Article  PubMed  CAS  Google Scholar 

  • Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE, Hofman A, Jensen S, Wang JJ, de Jong PT (2001) Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 108:697–704

    Article  PubMed  CAS  Google Scholar 

  • Smith W, Mitchell P, Leeder SR (2000) Dietary fat and fish intake and age-related maculopathy. Arch Ophthalmol 118:401–404

    PubMed  CAS  Google Scholar 

  • Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745

    Article  PubMed  CAS  Google Scholar 

  • Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt JC, Martone JF, Royall RM, Witt KA, Ezrine S (1991) Racial differences in the cause-specific prevalence of blindness in east Baltimore. N Engl J Med 325:1412–1417

    Article  PubMed  CAS  Google Scholar 

  • Souied EH, Benlian P, Amouyel P, Feingold J, Lagarde JP, Munnich A, Kaplan J, Coscas G, Soubrane G (1998) The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 125:353–359

    Article  PubMed  CAS  Google Scholar 

  • Souied EH, Ducroq D, Rozet JM, Gerber S, Perrault I, Munnich A, Coscas G, Soubrane G, Kaplan J (2000) ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 41:244–247

    PubMed  CAS  Google Scholar 

  • SST (2004) Health- and vision-related quality of life among patients with choroidal neovascularization secondary to age-related macular degeneration at enrollment in randomized trials of submacular surgery: SST Report No. 4. Am J Ophthalmol 138:91–108

    Article  Google Scholar 

  • Stone EM, Webster AR, Vandenburgh K, Streb LM, Hockey RR, Lotery AJ, Sheffield VC (1998) Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration. Nat Genet 20:328–329

    Article  PubMed  CAS  Google Scholar 

  • Stone EM, Lotery AJ, Munier FL, Heon E, Piguet B, Guymer RH, Vandenburgh K, Cousin P, Nishimura D, Swiderski RE, Silvestri G, Mackey DA, Hageman GS, Bird AC, Sheffield VC, Schorderet DF (1999) A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 22:199–202

    Article  PubMed  CAS  Google Scholar 

  • Stone EM, Braun TA, Russell SR, Kuehn MH, Lotery AJ, Moore PA, Eastman CG, Casavant TL, Sheffield VC (2004) Missense variations in the fibulin 5 gene and age-related macular degeneration. N Engl J Med 351:346–353

    Article  PubMed  CAS  Google Scholar 

  • Takahashi H, Shibuya M (2005) The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 109:227–241

    Article  CAS  Google Scholar 

  • Taylor HR, West S, Munoz B, Rosenthal FS, Bressler SB, Bressler NM (1992) The long-term effects of visible light on the eye. Arch Ophthalmol 110:99–104

    PubMed  CAS  Google Scholar 

  • Thurman JM, Holers VM (2006) The central role of the alternative complement pathway in human disease. J Immunol 176:1305–1310

    PubMed  CAS  Google Scholar 

  • Tielsch JM, Javitt JC, Coleman A, Katz J, Sommer A (1995) The prevalence of blindness and visual impairment among nursing home residents in Baltimore. N Engl J Med 332:1205–1209

    Article  PubMed  CAS  Google Scholar 

  • Tikellis G, Sun C, Gorin MB, Klein R, Klein BE, Larsen EK, Siscovick DS, Hubbard LD, Wong TY (2007) Apolipoprotein e gene and age-related maculopathy in older individuals: The Cardiovascular Health Study. Arch Ophthalmol 125:68–73

    Article  PubMed  CAS  Google Scholar 

  • Tuo J, Smith BC, Bojanowski CM, Meleth AD, Gery I, Csaky KG, Chew EY, Chan CC (2004) The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration. FASEB J 18(11):1297–1299

    PubMed  CAS  Google Scholar 

  • Uka J, Tamura H, Kobayashi T, Yamane K, Kawakami H, Minamoto A, Mishima HK (2006) No association of complement factor H gene polymorphism and age-related macular degeneration in the Japanese population. Retina 26:985–987

    Article  PubMed  Google Scholar 

  • van Leeuwen R, Vingerling JR, Hofman A, de Jong PT, Stricker BH (2003) Cholesterol lowering drugs and risk of age related maculopathy: prospective cohort study with cumulative exposure measurement. BMJ 326:255–256

    Article  PubMed  Google Scholar 

  • Varma R, Fraser-Bell S, Tan S, Klein R, Azen SP (2004) Prevalence of age-related macular degeneration in Latinos: The Los Angeles Latino Eye Study. Ophthalmology 111:1288–1297

    Article  PubMed  Google Scholar 

  • Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, de Jong P (1995) The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 102:205–210

    PubMed  CAS  Google Scholar 

  • Webster AR, Heon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM (2001) An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci 42:1179–1189

    PubMed  CAS  Google Scholar 

  • Weeks DE, Conley YP, Mah TS, Paul TO, Morse L, Ngo-Chang J, Dailey JP, Ferrell RE, Gorin MB (2000) A full genome scan for age-related maculopathy. Hum Mol Genet 9:1329–1349

    Article  PubMed  CAS  Google Scholar 

  • Weeks DE, Conley YP, Tsai HJ, Mah TS, Rosenfeld PJ, Paul TO, Eller AW, Morse LS, Dailey JP, Ferrell RE, Gorin MB (2001) Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. Am J Ophthalmol 132:682–92

    Article  PubMed  CAS  Google Scholar 

  • Wong TY, Shankar A, Klein R, Bray MS, Couper DJ, Klein BEK, Sharrett AR, Folsom AR (2006) Apolipoprotein E Gene and Early Age-Related Maculopathy: The Atherosclerosis Risk in Communities Study. Ophthalmology 113:255–259

    Article  PubMed  Google Scholar 

  • Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314:992–993

    Article  PubMed  CAS  Google Scholar 

  • Yoshida T, Dewan A, Zhang H, Sakamoto R, Okamoto H, Minami M, Obazawa M, Mizota A, Tanaka M, Saito Y, Takagi I, Hoh J, Iwata T (2007) HTRA1 promoter polymorphism predisposes Japanese to age-related macular degeneration. Mol Vis 13:545–548

    PubMed  CAS  Google Scholar 

  • Yuzawa M, Tamakoshi A, Kawamura T, Ohno Y, Uyama M, Honda T (1997) Report on the nationwide epidemiological survey of exudative age-related macular degeneration in Japan. Int Ophthalmol 21:1–3

    Article  PubMed  CAS  Google Scholar 

  • Zareparsi S, Reddick AC, Branham KE, Moore KB, Jessup L, Thoms S, Smith-Wheelock M, Yashar BM, Swaroop A (2004) Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest Ophthalmol Vis Sci 45:1306–1310

    Article  PubMed  Google Scholar 

  • Zareparsi S, Branham KE, Li M, Shah S, Klein RJ, Ott J, Hoh J, Abecasis GR, Swaroop A (2005a) Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 77:149–153

    Article  PubMed  CAS  Google Scholar 

  • Zareparsi S, Buraczynska M, Branham KE, Shah S, Eng D, Li M, Pawar H, Yashar BM, Moroi SE, Lichter PR, Petty HR, Richards JE, Abecasis GR, Elner VM, Swaroop A (2005b) Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet 14(11):1449–1455

    Article  PubMed  CAS  Google Scholar 

  • Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk LE, Lagali PS, Wong PW, MacDonald IM, Sieving PA, Figueroa DJ, Austin CP, Gould RJ, Ayyagari R, Petrukhin K (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 27:89–93

    PubMed  CAS  Google Scholar 

  • Zipfel PF (2001) Complement factor H: physiology and pathophysiology. Semin Thromb Hemost 27:191–199

    Article  PubMed  CAS  Google Scholar 

  • Zurdel J, Finckh U, Menzer G, Nitsch RM, Richard G (2002) CST3 genotype associated with exudative age related macular degeneration. Br J Ophthalmol 86:214–219

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrew Lotery.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lotery, A., Trump, D. Progress in defining the molecular biology of age related macular degeneration. Hum Genet 122, 219–236 (2007). https://doi.org/10.1007/s00439-007-0406-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-007-0406-3

Keywords

Navigation