Skip to main content
SpringerLink
Log in
Book cover

Age-related Macular Degeneration pp 33–43Cite as

Genetics

  • Chapter
  • First Online:

Abstract

In 1885, age-related macular degeneration (AMD) was first described as a clinical entity, characterized by age-dependent pigmentary and atrophic changes in the central area of the retina [1]. Today, AMD is known as one of the most frequent retinal disorders in industrialized countries and is a major cause of legal blindness [2]. Over the last decades, extraordinary efforts have been undertaken to elucidate the pathogenic mechanisms underlying the disease. A great number of clinical, pathological and experimental observations have been made, culminating in a first basic concept of disease pathology detailing the probable sequence of events in the process from a normally aging retina to the diseased state [3].

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

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

    Google Scholar 

  2. Friedman DS, O’Colmain BJ, Munoz B et al (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122(4):564–572

    Article  PubMed  Google Scholar 

  3. Zarbin MA (2004) Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 122:598–614

    Article  PubMed  Google Scholar 

  4. 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(3):321–327

    Article  PubMed  Google Scholar 

  5. Allikmets R, Shroyer NF, Singh N et al (1997) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277(5333):1805–1807

    Article  PubMed  CAS  Google Scholar 

  6. 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(1):200–206

    Article  PubMed  CAS  Google Scholar 

  7. Souied EH, Benlian P, Amouyel P et al (1998) The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 125(3):353–359

    Article  PubMed  CAS  Google Scholar 

  8. Edwards AO, Ritter R 3rd, Abel KJ et al (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308(5720):421–424

    Article  PubMed  CAS  Google Scholar 

  9. 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(20):7227–7232

    Article  PubMed  CAS  Google Scholar 

  10. Haines JL, Hauser MA, Schmidt S et al (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308(5720):419–421

    Article  PubMed  CAS  Google Scholar 

  11. Klein RJ, Zeiss C, Chew EY et al (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308(5720):385–389

    Article  PubMed  CAS  Google Scholar 

  12. Penfold PL, Killingsworth MC, Sarks SH (1985) Senile macular degeneration: the involvement of immunocompetent cells. Graefes Arch Clin Exp Ophthalmol 223(2):69–76

    Article  PubMed  CAS  Google Scholar 

  13. Schork NJ, Murray SS, Frazer KA, Topol EJ (2009) Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev 19(3):212–219

    Article  PubMed  CAS  Google Scholar 

  14. Ku CS, Loy EY, Pawitan Y, Chia KS (2010) The pursuit of genome-wide association studies: where are we now? J Hum Genet 55:195–206

    Article  PubMed  CAS  Google Scholar 

  15. Allikmets R, Singh N, Sun H et al (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15(3):236–246

    Article  PubMed  CAS  Google Scholar 

  16. Allikmets R (2000) Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am J Hum Genet 67(2):487–491

    Article  PubMed  CAS  Google Scholar 

  17. Haddad S, Chen CA, Santangelo SL, Seddon JM (2006) The genetics of age-related macular degeneration: a review of progress to date. Surv Ophthalmol 51(4):316–363

    Article  PubMed  Google Scholar 

  18. Baum L, Chan WM, Li WY et al (2003) ABCA4 sequence variants in Chinese patients with age-related macular degeneration or Stargardt’s disease. Ophthalmologica 217(2): 111–114

    Article  PubMed  CAS  Google Scholar 

  19. Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR (2001) Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. Hum Mol Genet 10(23):2671–2678

    Article  PubMed  CAS  Google Scholar 

  20. Strittmatter WJ, Saunders AM, Schmechel D et al (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90(5):1977–1981

    Article  PubMed  CAS  Google Scholar 

  21. Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537

    Article  PubMed  CAS  Google Scholar 

  22. Fritsche LG, Freitag-Wolf S, Bettecken T et al (2009) Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene. Hum Mutat 30(7):1048–1053

    Article  PubMed  CAS  Google Scholar 

  23. Schultz DW, Klein ML, Humpert A et al (2003) Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch Ophthalmol 121(5):679–683

    Article  PubMed  CAS  Google Scholar 

  24. Zareparsi S, Reddick AC, Branham KE et al (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(5):1306–1310

    Article  PubMed  Google Scholar 

  25. Hughes AE, Orr N, Esfandiary H et al (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 38(10):1173–1177

    Article  PubMed  CAS  Google Scholar 

  26. Schmid-Kubista KE, Tosakulwong N, Wu Y et al (2009) Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. Invest Ophthalmol Vis Sci 50(11):5070–5079

    Article  PubMed  Google Scholar 

  27. Giannakis E, Male DA, Ormsby RJ et al (2001) Multiple ligand binding sites on domain seven of human complement factor H. Int Immunopharmacol 1(3):433–443

    Article  PubMed  CAS  Google Scholar 

  28. Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41(4):355–367

    Article  PubMed  CAS  Google Scholar 

  29. Hecker LA, Edwards AO, Ryu E et al (2010) Genetic control of the alternative pathway of complement in humans and age-related macular degeneration. Hum Mol Genet 19(1):209–215

    Article  PubMed  CAS  Google Scholar 

  30. Johnson PT, Betts KE, Radeke MJ et al (2006) Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Proc Natl Acad Sci USA 103(46):17456–17461

    Article  PubMed  CAS  Google Scholar 

  31. Clark SJ, Higman VA, Mulloy B et al (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(34):24713–24720

    Article  PubMed  CAS  Google Scholar 

  32. Laine M, Jarva H, Seitsonen S et al (2007) Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J Immunol 178(6):3831–3836

    PubMed  CAS  Google Scholar 

  33. Skerka C, Lauer N, Weinberger AA et al (2007) Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 44(13):3398–3406

    Article  PubMed  CAS  Google Scholar 

  34. Yu J, Wiita P, Kawaguchi R et al (2007) Biochemical analysis of a common human polymorphism associated with age-related macular degeneration. Biochemistry 46(28):8451–8461

    Article  PubMed  CAS  Google Scholar 

  35. Skerka C, Zipfel PF (2008) Complement factor H related proteins in immune diseases. Vaccine 26(Suppl 8):I9–I14

    Article  PubMed  CAS  Google Scholar 

  36. Heinen S, Hartmann A, Lauer N et al (2009) Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 114(12):2439–2447

    Article  PubMed  CAS  Google Scholar 

  37. Gold B, Merriam JE, Zernant J et al (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38(4):458–462

    Article  PubMed  CAS  Google Scholar 

  38. Jakobsdottir J, Conley YP, Weeks DE, Ferrell RE, Gorin MB (2008) C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One 3:e2199

    Article  PubMed  Google Scholar 

  39. Maller J, George S, Purcell S et al (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 

  40. Spencer KL, Hauser MA, Olson LM et al (2007) Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet 16:1986–1992

    Article  PubMed  CAS  Google Scholar 

  41. Yates JRW, Sepp T, Matharu BK et al (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357:553–561

    Article  PubMed  CAS  Google Scholar 

  42. Montes T, Tortajada A, Morgan BP, Rodriguez de Cordoba S, Harris CL (2009) Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc Natl Acad Sci USA 106(11):4366–4371

    Article  PubMed  CAS  Google Scholar 

  43. Despriet DDG, van Duijn CM, Oostra BA et al (2009) Complement component C3 and risk of age-related macular degeneration. Ophthalmology 116:474–480

    Article  PubMed  Google Scholar 

  44. Spencer KL, Olson LM, Anderson BM et al (2008) C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet 17(12):1821–1824

    Article  PubMed  CAS  Google Scholar 

  45. Arvilommi H (1974) Capacity of complement c3 phenotypes to bind on to mononuclear cells in man. Nature 251(5477):740–741

    Article  PubMed  CAS  Google Scholar 

  46. Botto M, Fong KY, So AK, Koch C, Walport MJ (1990) Molecular basis of polymorphisms of human complement component C3. J Exp Med 172(4):1011–1017

    Article  PubMed  CAS  Google Scholar 

  47. Fagerness J, Maller JB, Neale BM et al (2009) Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 17:100–104

    Article  PubMed  CAS  Google Scholar 

  48. Jakobsdottir J, Conley YP, Weeks DE et al (2005) Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 77:389–407

    Article  PubMed  CAS  Google Scholar 

  49. Rivera A, Fisher SA, Fritsche LG et al (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(21):3227–3236

    Article  PubMed  CAS  Google Scholar 

  50. Dewan A, Liu M, Hartman S et al (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314(5801):989–992

    Article  PubMed  CAS  Google Scholar 

  51. Yang Z, Tong Z, Chen Y et al (2010) Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS Genet 6:e1000836

    Article  PubMed  Google Scholar 

  52. Fritsche LG, Loenhardt T, Janssen A et al (2008) Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 40(7):892–896

    Article  PubMed  CAS  Google Scholar 

  53. Grau S, Richards PJ, Kerr B et al (2006) The role of human HtrA1 in arthritic disease. J Biol Chem 281(10):6124–6129

    Article  PubMed  CAS  Google Scholar 

  54. An E, Sen S, Park SK, Gordish-Dressman H, Hathout Y (2010) Identification of novel substrates for the serine protease HTRA1 in the human RPE secretome. Invest Ophthalmol Vis Sci 51(7):3379–3386, Epub 2010 Mar 5

    Article  PubMed  Google Scholar 

  55. Oka C, Tsujimoto R, Kajikawa M et al (2004) HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins. Development 131(5):1041–1053

    Article  PubMed  CAS  Google Scholar 

  56. Chien J, Staub J, Hu SI et al (2004) A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene 23(8):1636–1644

    Article  PubMed  CAS  Google Scholar 

  57. He X, Ota T, Liu P et al (2010) Downregulation of HtrA1 promotes resistance to anoikis and peritoneal dissemination of ovarian cancer cells. Cancer Res 70(8):3109–3118

    Article  PubMed  CAS  Google Scholar 

  58. Chan CC, Shen D, Zhou M et al (2007) Human HtrA1 in the archived eyes with age-related macular degeneration. Trans Am Ophthalmol Soc 105:92–97; discussion 97–98

    PubMed  Google Scholar 

  59. Cameron DJ, Yang Z, Gibbs D et al (2007) HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration. Cell Cycle 6(9): 1122–1125

    Article  PubMed  CAS  Google Scholar 

  60. Kanda A, Chen W, Othman M et al (2007) A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA 104(41):16227–16232

    Article  PubMed  CAS  Google Scholar 

  61. Yang Z, Camp NJ, Sun H et al (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314(5801):992–993

    Article  PubMed  CAS  Google Scholar 

  62. Friedrich U, Myers C, Fritsche LG et al (2011) Risk and non risk associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency. Hum Mol Genet 20(7):1387–1399

    Google Scholar 

  63. Francis PJ, Appukuttan B, Simmons E et al (2008) Rhesus monkeys and humans share common susceptibility genes for age-related macular disease. Hum Mol Genet 17(17):2673–2680

    Article  PubMed  CAS  Google Scholar 

  64. Kortvely E, Hauck SM, Duetsch G et al (2010) ARMS2 is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degenerations. Invest Ophthalmol Vis Sci 51(1):79–88

    Article  PubMed  Google Scholar 

  65. Wang G, Spencer KL, Court BL et al (2009) Localization of age-related macular degeneration-associated ARMS2 in cytosol, not mitochondria. Invest Ophthalmol Vis Sci 50(7):3084–3090

    Article  PubMed  Google Scholar 

  66. Chen W, Stambolian D, Edwards AO et al (2010) Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci USA 107:7401–7406

    Article  PubMed  CAS  Google Scholar 

  67. Neale BM, Fagerness J, Reynolds R et al (2010) Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci USA 107:7395–7400

    Article  PubMed  CAS  Google Scholar 

  68. Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U (1994) Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby’s fundus dystrophy. Nat Genet 8(4):352–356

    Article  PubMed  CAS  Google Scholar 

  69. Baird PN, Hageman GS, Guymer RH (2009) New era for personalized medicine: the diagnosis and management of age-related macular degeneration. Clin Exp Ophthalmol 37(8):814–821

    Article  Google Scholar 

  70. Conley YP, Jakobsdottir J, Mah T et al (2006) CFH, ELOVL4, PLEKHA1 and LOC387715 genes and ­susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet 15(21):3206–3218

    Article  PubMed  CAS  Google Scholar 

  71. 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(1):55–62

    Article  PubMed  CAS  Google Scholar 

  72. 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(1):149–153

    Article  PubMed  CAS  Google Scholar 

  73. Chen LJ, Liu DTL, Tam POS et al (2006) Association of complement factor H polymorphisms with exudative age-related macular degeneration. Mol Vis 12:1536–1542

    PubMed  CAS  Google Scholar 

  74. Mori K, Gehlbach PL, Kabasawa S et al (2007) Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population. Invest Ophthalmol Vis Sci 48:5315–5319

    Article  PubMed  Google Scholar 

  75. Li M, Atmaca-Sonmez P, Othman M et al (2006) CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 38(9):1049–1054

    Article  PubMed  CAS  Google Scholar 

  76. Hageman GS, Hancox LS, Taiber AJ et al (2006) Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 38:592–604

    Article  PubMed  CAS  Google Scholar 

  77. Ross RJ, Bojanowski CM, Wang JJ et al (2007) The LOC387715 polymorphism and age-related macular degeneration: replication in three case–control samples. Invest Ophthalmol Vis Sci 48:1128–1132

    Article  PubMed  Google Scholar 

  78. Hadley D, Orlin A, Brown G et al (2010) Analysis of six genetic risk factors highly associated with AMD in the region surrounding ARMS2 and HTRA1 on chromosome 10, region q26. Invest Ophthalmol Vis Sci 51:2191–2196

    Article  PubMed  Google Scholar 

  79. Gotoh N, Nakanishi H, Hayashi H et al (2009) ARMS2 (LOC387715) variants in Japanese patients with exudative age-related macular degeneration and polypoidal choroidal vasculopathy. Am J Ophthalmol 147:1037–1041, 1041.e1–1041.e2

    Article  PubMed  CAS  Google Scholar 

  80. Ricci F, Zampatti S, D’Abbruzzi F et al (2009) Typing of ARMS2 and CFH in age-related macular degeneration: case–control study and assessment of frequency in the Italian population. Arch Ophthalmol 127:1368–1372

    Article  PubMed  CAS  Google Scholar 

  81. McKay GJ, Dasari S, Patterson CC, Chakravarthy U, Silvestri G (2010) Complement component 3: an assessment of association with AMD and analysis of gene-gene and gene-environment interactions in a Northern Irish cohort. Mol Vis 16:194–199

    PubMed  CAS  Google Scholar 

  82. Baird PN, Guida E, Chu DT, Vu HT, Guymer RH (2004) The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 45(5):1311–1315

    Article  PubMed  Google Scholar 

  83. 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(4):209–223

    Article  PubMed  Google Scholar 

  84. 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  CAS  Google Scholar 

  85. Simonelli F, Margaglione M, Testa F et al (2001) Apolipoprotein E polymorphisms in age-related macular degeneration in an Italian population. Ophthalmic Res 33(6): 325–328

    Article  PubMed  CAS  Google Scholar 

  86. Thakkinstian A, Bowe S, McEvoy M, Smith W, Attia J (2006) Association between apolipoprotein E polymorphisms and age-related macular degeneration: a HuGE review and meta-analysis. Am J Epidemiol 164:813–822

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Human Genetics, University of Regensburg, Regensburg, Germany

    L. G. Fritsche, U. Friedrich & B. H. F. Wxeber

Authors
  1. L. G. Fritsche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U. Friedrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. H. F. Wxeber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. H. F. Wxeber .

Editor information

Editors and Affiliations

  1. Universitäts-Augenklinik Bonn, Universitätsklinikum Bonn, Ernst-Abbe-Str. 2, Bonn, 53127, Germany

    Frank G. Holz

  2. Zentrum für Refraktive Chirurgie, Hohenzollern-Klinik, Hohenzollernring 57, Münster, 48145, Germany

    Daniel Pauleikhoff

  3. Consultants of New York, Vitreous, Retina & Macula, Park Avenue 460, New York, 10022, New York, USA

    Richard F. Spaide

  4. , Deptartment of Ophthalmology, Moorfields Eye Hospital, City Road, London, EC1V 2PD, United Kingdom

    Alan C. Bird

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Fritsche, L.G., Friedrich, U., Wxeber, B.H.F. (2013). Genetics. In: Holz, F., Pauleikhoff, D., Spaide, R., Bird, A. (eds) Age-related Macular Degeneration. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-22107-1_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-22107-1_2

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-22106-4

  • Online ISBN: 978-3-642-22107-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation