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Y402H-Polymorphismus im Komplementfaktor H und altersabhängige Makuladegeneration (AMD)

Y402H polymorphism in complement factor H and age-related macula degeneration (AMD)

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Zusammenfassung

Die altersabhängige Makuladegeneration (AMD) ist eine genetisch komplexe Erkrankung. Neuere Untersuchungen legen nahe, dass sie zu mehr als zwei Dritteln auf genetische Ursachen zurückzuführen ist. Umfangreiche molekulargenetische Studien (Kandidatengenanalysen, Kopplungsanalysen und Assoziationsstudien) wurden in den letzten Jahren durchgeführt, um die genetischen Faktoren einer AMD-Prädisposition auf molekularer Ebene zu beschreiben. Kürzlich ist es nun gelungen, im Komplementfaktor-H- (CFH-)Gen ein hochsignifikantes Risikoallel, Y402H, zu identifizieren. Das relative Risiko für die Entwicklung einer AMD wird auf 2,4–4,6 für heterozygote Träger des Risikoallels geschätzt und auf 3,3–7,4 für Homozygote. Dieser Polymorphismus trägt demnach etwa 20–50% zum AMD-Gesamtrisiko bei und erklärt somit einen wesentlichen Teil des genetischen Beitrags. Dieser Übersichtsartikel berichtet über den Stand der genetischen Forschung zur AMD und stellt die neuen Ergebnisse zum CFH-Gen dar.

Abstract

Age-related macular degeneration is a complex genetic disorder. Recent data suggest that the additive genetic risk for late-stage disease is more than two-thirds. Comprehensive genetic studies (candidate gene approaches, linkage and association studies) have been performed in recent years to identity the genetic risk factors at the molecular lavel. Very recently, a significant risk allele, Y402H, has been discovered in the complement factor H (CFH) gene. The relative risk of developing AMD has been estimated between 2.4–4.6 for heterozygotes and 3.3–7.4 for homozygotes. This polymorphism accounts for approximately 20–50% of the overall risk of developing AMD. In this review the results from molecular genetic studies in AMD are summarized, with a special emphasis on the recent data obtained for the CFH gene.

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Literatur

  1. Abecasis GR, Yashar BM, Zhao Y et al. (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

    PubMed  Google Scholar 

  2. Allikmets R, Shroyer NF, Singh N et al. (1997) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277:1805–1807

    Google Scholar 

  3. Allikmets R, Seddon JM, Bernstein PS et al. (1999) Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies. Hum Genet 104:449–453

    PubMed  Google Scholar 

  4. Attebo K, Mitchell P, Smith W (1996) Visual acuity and the causes of visual loss in Australia. The Blue Mountains Eye Study. Ophthalmology 103:357–364

    PubMed  Google Scholar 

  5. Ayyagari R, Zhang K, Hutchinson A et al. (2001) Evaluation of the ELOVL4 gene in patients with age-related macular degeneration. Ophthalmic Genet 22:233–239

    PubMed  Google Scholar 

  6. Bressler NM, Bressler SB, West SK, Fine SL, Taylor HR (1989) The grading and prevalence of macular degeneration in Chesapeake Bay watermen. Arch Ophthalmol 107:847–852

    PubMed  Google Scholar 

  7. Cichon S, Freudenberg J, Nöthen MM, Propping P (2002) Variabilität im menschlichen Genom: Bedeutung für die Krankheitsforschung. Dtsch Ärztebl A3091–3101

  8. 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

    PubMed  Google Scholar 

  9. Daiger SP (2005) Genetics. Was the human genome project worth the effort? Science 308:362–364

    Google Scholar 

  10. De Jong PT, Klaver CC, Wolfs RC, Assink JJ, Hofman A (1997) Familial aggregation of age-related maculopathy. Am J Ophthalmol 124:862–863

    PubMed  Google Scholar 

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

    Google Scholar 

  12. Esparza-Gordillo J, Soria JM, Buil A, Almasy L, Blangero J, Fontcuberta J, Rodriguez de CS (2004) Genetic and environmental factors influencing the human factor H plasma levels. Immunogenetics 56:77–82

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  14. Felbor U, Doepner D, Schneider U, Zrenner E, Weber BH (1997) Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies. Invest Ophthalmol Vis Sci 38:1054–1059

    PubMed  Google Scholar 

  15. Fisher SA, Abecasis GR, Yashar BM et al. (2005) Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet 14:2257–2264

    PubMed  Google Scholar 

  16. Freudenberg J, Cichon S, Nöthen MM, Propping P (2002) Die neu entdeckte Blockstruktur des menschlichen Genoms. Ein Organisationsprinzip der genetischen Variabilität. Dtsch Ärztebl A3190–3195

  17. Gass JD (1973) Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 90:206–217

    PubMed  Google Scholar 

  18. Gorin MB, Breitner JC, de Jong PT, Hageman GS, Klaver CC, Kuehn MH, Seddon JM (1999) The genetics of age-related macular degeneration. Mol Vis 5:29

    PubMed  Google Scholar 

  19. Hageman GS, Luthert PJ, Chong NHV, Johnson LV, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20:705–732

    PubMed  Google Scholar 

  20. Hageman GS, Anderson DH, Johnson LV et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102:7227–7232

    Article  PubMed  Google Scholar 

  21. Haines JL, Hauser MA, Schmidt S et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–421

    Google Scholar 

  22. 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

    PubMed  Google Scholar 

  23. Hekimi S, Guarente L (2003) Genetics and the specificity of the aging process. Science 299:1351–1354

    Google Scholar 

  24. Hyman LG, Lilienfeld AM, Ferris FL, Fine SL (1983) Senile macular degeneration: a case-control study. Am J Epidemiol 118:213–227

    PubMed  Google Scholar 

  25. Iyengar SK, Song D, Klein BE et al. (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  Google Scholar 

  26. 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

    PubMed  Google Scholar 

  27. Klaver CC, Kliffen M, van Duijn CM et al. (1998) Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 63:200–206

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  29. Klein BE, Klein R, Linton KL (1992) Prevalence of age-related lens opacities in a population. The Beaver Dam Eye Study. Ophthalmology 99:546–552

    PubMed  Google Scholar 

  30. Klein ML, Schultz DW, Edwards A et al. (1998) Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol 116:1082–1088

    PubMed  Google Scholar 

  31. Klein R, Klein BE, Tomany SC, Meuer SM, Huang GH (2002) Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study. Ophthalmology 109:1767–1779

    PubMed  Google Scholar 

  32. Klein RJ, Zeiss C, Chew EY et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389

    Google Scholar 

  33. Kramer F, White K, Pauleikhoff D et al. (2000) Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration. Eur J Hum Genet 8:286–292

    PubMed  Google Scholar 

  34. Lotery AJ, Munier FL, Fishman GA et al. (2000) Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. Invest Ophthalmol Vis Sci 41:1291–1296

    PubMed  Google Scholar 

  35. Majewski J, Schultz DW, Weleber RG et al. (2003) Age-related macular degeneration — a genome scan in extended families. Am J Hum Genet 73:540–550

    PubMed  Google Scholar 

  36. 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  Google Scholar 

  37. 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  Google Scholar 

  38. Ozaki K, Ohnishi Y, Iida A et al. (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32:650–654

    Article  PubMed  Google Scholar 

  39. Rivera A, White K, Stohr H et al. (2000) A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet 67:800–813

    PubMed  Google Scholar 

  40. 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

    PubMed  Google Scholar 

  41. Sauer CG, White K, Stohr H et al. (2001) Evaluation of the G protein coupled receptor-75 (GPR75) in age related macular degeneration. Br J Ophthalmol 85:969–975

    PubMed  Google Scholar 

  42. Schick JH, Iyengar SK, Klein BE et al. (2003) A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet 72:1412–1424

    PubMed  Google Scholar 

  43. Schmidt S, Saunders AM, De La Paz MA et al. (2000) Association of the apolipoprotein E gene with age-related macular degeneration: possible effect modification by family history, age, and gender. Mol Vis 6:287–293

    PubMed  Google Scholar 

  44. Schmidt S, Klaver C, Saunders A et al. (2002) A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 23:209–223

    PubMed  Google Scholar 

  45. Seddon JM, Ajani UA, Mitchell BD (1997) Familial aggregation of age-related maculopathy. Am J Ophthalmol 123:199–206

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  47. Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N (2004) Association between C-reactive protein and age-related macular degeneration. JAMA 291:704–710

    PubMed  Google Scholar 

  48. 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

    PubMed  Google Scholar 

  49. Shastry BS, Trese MT (1999) Evaluation of the peripherin/RDS gene as a candidate gene in families with age-related macular degeneration. Ophthalmologica 213:165–170

    PubMed  Google Scholar 

  50. Silvestri G (1997) Age-related macular degeneration: genetics and implications for detection and treatment. Mol Med Today 3:84–91

    PubMed  Google Scholar 

  51. 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

    PubMed  Google Scholar 

  52. Stone EM, Braun TA, Russell SR et al. (2004) Missense variations in the fibulin 5 gene and age-related macular degeneration. N Engl J Med 351:346–353

    PubMed  Google Scholar 

  53. Stone EM, Lotery AJ, Munier FL et al. (1999) A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 22:199–202

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  55. Vingerling JR, Klaver CC, Hofman A, de Jong PT (1995) Epidemiology of age-related maculopathy. Epidemiol Rev 17:347–360

    PubMed  Google Scholar 

  56. Weeks DE, Conley YP, Mah TS et al. (2000) A full genome scan for age-related maculopathy. Hum Mol Genet 9:1329–1349

    PubMed  Google Scholar 

  57. Weeks DE, Conley YP, Tsai HJ et al. (2001) Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. Am J Ophthalmol 132:682–692

    PubMed  Google Scholar 

  58. Weeks DE, Conley YP, Tsai HJ et al. (2004) Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. Am J Hum Genet 75:174–189

    PubMed  Google Scholar 

  59. White K, Marquardt A, Weber BH (2000) VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies. Hum Mutat 15:301–308

    PubMed  Google Scholar 

  60. Yates JR, Moore AT (2000) Genetic susceptibility to age related macular degeneration. J Med Genet 37:83–87

    PubMed  Google Scholar 

  61. Yoshida S, Yashar BM, Hiriyanna S, Swaroop A (2002) Microarray analysis of gene expression in the aging human retina. Invest Ophthalmol Vis Sci 43:2554–2560

    PubMed  Google Scholar 

  62. Zareparsi S, Branham KE, Li M et al. (2005) 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

    PubMed  Google Scholar 

  63. Zareparsi S, Buraczynska M, Branham KE et al. (2005) Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet 14:1449–1455

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Augenklinik, Universität, Bonn

    H. P. N. Scholl & F. G. Holz

  2. Institut für Humangenetik, Universität, Regensburg

    B. H. F. Weber

  3. Abteilung für Genomik, Forschungszentrum Life & Brain der Universität, Bonn

    M. M. Nöthen

  4. Institut für Medizinische Biometrie und Informatik und Epidemiologie, Universität, Bonn

    T. Wienker

  5. Augenklinik, Universität, Ernst-Abbe-Straße 2, 53127 , Bonn

    H. P. N. Scholl

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  1. H. P. N. Scholl
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  2. B. H. F. Weber
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  3. M. M. Nöthen
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  4. T. Wienker
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  5. F. G. Holz
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Correspondence to H. P. N. Scholl.

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Unterstützt durch: Europäische Gemeinschaft (EU) FP5, QoL, KA6, Concerted Action QLRT-2001–02494 „PHOTAGE“; EU FP6, Integrated Project „EVI-GENORET“ (LSHG-CT-2005–5120; Vertragsnummer 512036); Deutsche Forschungsgemeinschaft (DFG) Heisenberg-Stipendium SCHO 734/2–1; DFG Ho 1926/1–3; We 1259/14–3; DFG Schwerpunktprogramm „Altersabhängige Makuladegeneration“ SPP 1088; Ruth and Milton Steinbach Fund (BHFW).

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Scholl, H.P.N., Weber, B.H.F., Nöthen, M.M. et al. Y402H-Polymorphismus im Komplementfaktor H und altersabhängige Makuladegeneration (AMD). Ophthalmologe 102, 1029–1035 (2005). https://doi.org/10.1007/s00347-005-1270-y

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