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The hypothetical molecular mechanism of the ethnic variations in the manifestation of age-related macular degeneration; focuses on the functions of the most significant susceptibility genes

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Abstract

Age-related macular degeneration (AMD) is the leading sight-threatening disease in developed countries. On the other hand, recent studies indicated an ethnic variation in the phenotype of AMD. For example, several reports demonstrated that the incidence of drusen in AMD patients is less in Asians compared to Caucasians though the reason has not been clarified yet. In the last decades, several genome association studies have disclosed many susceptible genes of AMD and revealed that the association strength of some genes was different among races and AMD phenotypes. In this review article, the essential findings of the clinical studies and genome association studies for the most significant genes CFH and ARMS2/HTRA1 in AMD of different races are summarized, and theoretical hypotheses about the molecular mechanisms underlying the ethnic variation in the AMD manifestation mainly focused on those genes between Caucasians and Asians are discussed.

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References

  1. Klein R, Klein BEK, Knudtson MD, Meuer SM, Swift M, Gangnon RE (2007) Fifteen-year cumulative incidence of age-related macular degeneration: The beaver dam eye study. Ophthalmology 114:253–262. https://doi.org/10.1016/j.ophtha.2006.10.040

    Article  PubMed  Google Scholar 

  2. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2:e106-116. https://doi.org/10.1016/S2214-109X(13)70145-1

    Article  PubMed  Google Scholar 

  3. Abdelsalam A, Del Priore L, Zarbin MA (1999) Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced regression. Surv Ophthalmol 44:1–29. https://doi.org/10.1016/s0039-6257(99)00072-7

    Article  CAS  PubMed  Google Scholar 

  4. Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, Milton RC, Bressler SB, Klein R, Age-Related Eye Disease Study (AREDS) Research Group (2005) A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 123:1570–1574. https://doi.org/10.1001/archopht.123.11.1570

    Article  PubMed  Google Scholar 

  5. Yannuzzi LA, Negrão S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter J, Freund KB, Sorenson J, Orlock D, Borodoker N (2001) Retinal angiomatous proliferation in age–related macular degeneration. Retina 21:416–434. https://doi.org/10.1097/00006982-200110000-00003

    Article  CAS  PubMed  Google Scholar 

  6. Sho K, Takahashi K, Yamada H, Wada M, Nagai Y, Otsuji T, Nishikawa M, Mitsuma Y, Yamazaki Y, Matsumura M, Uyama M (2003) Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics. Arch Ophthalmol 121:1392–1396. https://doi.org/10.1001/archopht.121.10.1392

    Article  PubMed  Google Scholar 

  7. Bessho H, Honda S, Imai H, Negi A (2011) Natural course and funduscopic findings of polypoidal choroidal vasculopathy in a Japanese population over 1 year of follow-up. Retina 31:1598–1602. https://doi.org/10.1097/IAE.0b013e31820d3f28

    Article  PubMed  Google Scholar 

  8. Joachim N, Mitchell P, Younan C, Burlutsky G, Cheng CY, Cheung CM, Zheng Y, Moffitt M, Wong TY, Wang JJ (2014) Ethnic variation in early age-related macular degeneration lesions between white Australians and Singaporean Asians. Invest Ophthalmol Vis Sci 55:4421–4429. https://doi.org/10.1167/iovs.14-14476

    Article  PubMed  Google Scholar 

  9. Yanagi Y, Foo VHX, Yoshida A (2019) Asian age-related macular degeneration: from basic science research perspective. Eye (Lond) 33:34–49. https://doi.org/10.1038/s41433-018-0225-x

    Article  PubMed  Google Scholar 

  10. Cheung CMG, Lee WK, Koizumi H, Dansingani K, Lai TYY, Freund KB (2019) Pachychoroid disease. Eye (Lond) 33:14–33. https://doi.org/10.1038/s41433-018-0158-4

    Article  PubMed  Google Scholar 

  11. Baek J, Kook L, Lee WK (2019) Choriocapillaris flow impairments in association with pachyvessel in early stages of pachychoroid. Sci Rep 9:5565. https://doi.org/10.1038/s41598-019-42052-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yanagi Y (2020) Pachychoroid disease: a new perspective on exudative maculopathy. Jpn J Ophthalmol 64:323–337. https://doi.org/10.1007/s10384-020-00740-5

    Article  PubMed  Google Scholar 

  13. Matsumoto H, Hoshino J, Mukai R, Nakamura K, Kishi S, Akiyama H (2022) Clinical characteristics and pachychoroid incidence in Japanese patients with neovascular age-related macular degeneration. Sci Rep 12:4492. https://doi.org/10.1038/s41598-022-08666-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sasaki M, Kawasaki R, Yanagi Y (2022) Early stages of age-related macular degeneration: racial/ethnic differences and proposal of a new classification incorporating emerging concept of choroidal pathology. J Clin Med 11:6274. https://doi.org/10.3390/jcm11216274

    Article  PubMed  PubMed Central  Google Scholar 

  15. Terao N, Koizumi H, Kojima K, Yamagishi T, Yamamoto Y, Yoshii K, Kitazawa K, Hiraga A, Toda M, Kinoshita S, Sotozono C, Hamuro J (2018) Distinct aqueous humour cytokine profiles of patients with pachychoroid neovasculopathy and neovascular age-related macular degeneration. Sci Rep 8:10520. https://doi.org/10.1038/s41598-018-28484-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424. https://doi.org/10.1126/science.1110189

    Article  CAS  PubMed  Google Scholar 

  17. 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 U S A 102:7227–7232. https://doi.org/10.1073/pnas.0501536102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 308:419–21. https://doi.org/10.1126/science.1110359

    Article  CAS  PubMed  Google Scholar 

  19. Maugeri A, Barchitta M, Agodi A (2019) The association between complement factor H rs1061170 polymorphism and age-related macular degeneration: a comprehensive meta-analysis stratified by stage of disease and ethnicity. Acta Ophthalmol 97:e8–e21. https://doi.org/10.1111/aos.13849

    Article  CAS  PubMed  Google Scholar 

  20. Kondo N, Bessho H, Honda S, Negi A (2011) Complement factor H Y402H variant and risk of age-related macular degeneration in Asians: a systematic review and meta-analysis. Ophthalmology 118:339–344. https://doi.org/10.1016/j.ophtha.2010.06.040

    Article  PubMed  Google Scholar 

  21. Arakawa S, Takahashi A, Ashikawa K, Hosono N, Aoi T, Yasuda M, Oshima Y, Yoshida S, Enaida H, Tsuchihashi T, Mori K, Honda S, Negi A, Arakawa A, Kadonosono K, Kiyohara Y, Kamatani N, Nakamura Y, Ishibashi T, Kubo M (2011) Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nat Genet 43:1001–1004. https://doi.org/10.1038/ng.938

    Article  CAS  PubMed  Google Scholar 

  22. Ruamviboonsuk P, Tadarati M, Singhanetr P, Wattanapokayakit S, Kunhapan P, Wanitchanon T, Wichukchinda N, Mushiroda T, Akiyama M, Momozawa Y, Kubo M, Mahasirimongkol S (2017) Genome-wide association study of neovascular age-related macular degeneration in the Thai population. J Hum Genet 62:957–962. https://doi.org/10.1038/jhg.2017.72

    Article  PubMed  Google Scholar 

  23. Yuan D, Yang Q, Liu X, Yuan D, Yuan S, Xie P, Liu Q (2013) Complement factor H Val62Ile variant and risk of age-related macular degeneration: a meta-analysis. Mol Vis 19:374–383

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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. https://doi.org/10.1093/hmg/ddi353

    Article  CAS  PubMed  Google Scholar 

  25. 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. https://doi.org/10.1126/science.1133811

    Article  CAS  PubMed  Google Scholar 

  26. Sobrin L, Ripke S, Yu Y et al (2012) Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes. Ophthalmology 119:1874–1885. https://doi.org/10.1016/j.ophtha.2012.03.014

    Article  PubMed  Google Scholar 

  27. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314:989–992. https://doi.org/10.1126/science.1133807

    Article  CAS  PubMed  Google Scholar 

  28. Yanagisawa S, Kondo N, Miki A, Matsumiya W, Kusuhara S, Tsukahara Y, Honda S, Negi A (2011) Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2). Mol Vis 17:3574–3582

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yuan D, Yuan D, Yuan S, Liu Q (2013) The age-related maculopathy susceptibility 2 polymorphism and polypoidal choroidal vasculopathy in Asian populations: a meta-analysis. Ophthalmology 120:2051–2057. https://doi.org/10.1016/j.ophtha.2013.03.026

    Article  PubMed  Google Scholar 

  30. Fan Q, Cheung CMG, Chen LJ, Yamashiro K, Ahn J, Laude A, Mathur R, Mun CC, Yeo IY, Lim TH, Teo YY, Khor CC, Park KH, Yoshimura N, Pang CP, Wong TY, Cheng CY (2017) Shared genetic variants for polypoidal choroidal vasculopathy and typical neovascular age-related macular degeneration in East Asians. J Hum Genet 62:1049–1055. https://doi.org/10.1038/jhg.2017.83

    Article  PubMed  Google Scholar 

  31. Kondo N, Honda S, Ishibashi K, Tsukahara Y, Negi A (2007) LOC387715/HTRA1 variants in polypoidal choroidal vasculopathy and age-related macular degeneration in a Japanese population. Am J Ophthalmol 144:608–612. https://doi.org/10.1016/j.ajo.2007.06.003

    Article  CAS  PubMed  Google Scholar 

  32. Shin HT, Yoon BW, Seo JH (2021) Comparison of risk allele frequencies of single nucleotide polymorphisms associated with age-related macular degeneration in different ethnic groups. BMC Ophthalmol 21:97. https://doi.org/10.1186/s12886-021-01830-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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. https://doi.org/10.1126/science.1109557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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. https://doi.org/10.1126/science.1110359

    Article  CAS  PubMed  Google Scholar 

  35. 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. https://doi.org/10.1038/ng1873

    Article  CAS  PubMed  Google Scholar 

  36. Honda S, Matsumiya W, Negi A (2014) Polypoidal choroidal vasculopathy: clinical features and genetic predisposition. Ophthalmologica 231:59–74. https://doi.org/10.1159/000355488

    Article  PubMed  Google Scholar 

  37. Spaide RF (2018) Disease expression in nonexudative age-related macular degeneration varies with choroidal thickness. Retina 38:708–716. https://doi.org/10.1097/IAE.0000000000001689

    Article  PubMed  Google Scholar 

  38. Fukuda Y, Sakurada Y, Yoneyama S, Kikushima W, Sugiyama A, Matsubara M, Tanabe N, Iijima H (2019) Clinical and genetic characteristics of pachydrusen in patients with exudative age-related macular degeneration. Sci Rep 9:11906. https://doi.org/10.1038/s41598-019-48494-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Matsumoto H, Mukai R, Morimoto M, Tokui S, Kishi S, Akiyama H (2019) Clinical characteristics of pachydrusen in central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol 257:1127–1132. https://doi.org/10.1007/s00417-019-04284-4

    Article  CAS  PubMed  Google Scholar 

  40. Pang CE, Freund KB (2015) Pachychoroid neovasculopathy. Retina 35:1–9. https://doi.org/10.1097/IAE.0000000000000331

    Article  CAS  PubMed  Google Scholar 

  41. Deng Y, Qiao L, Du M, Qu C, Wan L, Li J, Huang L (2021) Age-related macular degeneration: epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy. Genes Dis 9:62–79. https://doi.org/10.1016/j.gendis.2021.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Winkler TW, Grassmann F, Brandl C et al (2020) Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease. BMC Med Genomics 13:120. https://doi.org/10.1186/s12920-020-00760-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miki A, Kondo N, Yanagisawa S, Bessho H, Honda S, Negi A (2014) Common variants in the complement factor H gene confer genetic susceptibility to central serous chorioretinopathy. Ophthalmology 121:1067–1072. https://doi.org/10.1016/j.ophtha.2013.11.020

    Article  PubMed  Google Scholar 

  44. Hosoda Y, Yoshikawa M, Miyake M, Tabara Y, Ahn J, Woo SJ, Honda S, Sakurada Y, Shiragami C, Nakanishi H, Oishi A, Ooto S, Miki A; Nagahama Study Group; Iida T, Iijima H, Nakamura M, Khor CC, Wong TY, Song K, Park KH, Yamada R, Matsuda F, Tsujikawa A, Yamashiro K (2018) CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy. Proc Natl Acad Sci U S A 115:6261–6266. https://doi.org/10.1073/pnas.1802212115

    Article  CAS  Google Scholar 

  45. Ionita-Laza I, Lange C, Laird NM (2009) Estimating the number of unseen variants in the human genome. Proc Natl Acad Sci U S A 106:5008–5013. https://doi.org/10.1073/pnas.0807815106

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  46. Rigden DJ, Fernández XM (2023) The 2023 Nucleic Acids Research Database Issue and the online molecular biology database collection. Nucleic Acids Res 51:D1–D8. https://doi.org/10.1093/nar/gkac1186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kondo N, Honda S, Kuno S, Negi A (2009) Coding variant I62V in the complement factor H gene is strongly associated with polypoidal choroidal vasculopathy. Ophthalmology 116:304–310. https://doi.org/10.1016/j.ophtha.2008.11.011

    Article  PubMed  Google Scholar 

  48. Okamoto H, Umeda S, Obazawa M, Minami M, Noda T, Mizota A, Honda M, Tanaka M, Koyama R, Takagi I, Sakamoto Y, Saito Y, Miyake Y, Iwata T (2006) Complement factor H polymorphisms in Japanese population with age-related macular degeneration. Mol Vis 12:156–158

    CAS  PubMed  Google Scholar 

  49. 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. https://doi.org/10.1007/s00439-006-0187-0

    Article  CAS  PubMed  Google Scholar 

  50. Fuse N, Miyazawa A, Mengkegale M, Yoshida M, Wakusawa R, Abe T, Tamai M (2006) Polymorphisms in complement factor H and Hemicentin-1 genes in a Japanese population with dry-type age-related macular degeneration. Am J Ophthalmol 142:1074–1076. https://doi.org/10.1016/j.ajo.2006.07.030

    Article  CAS  PubMed  Google Scholar 

  51. Gotoh N, Nakanishi H, Hayashi H, Yamada R, Otani A, Tsujikawa A, Yamashiro K, Tamura H, Saito M, Saito K, Iida T, Matsuda F, Yoshimura N (2009) ARMS2 (LOC387715) variants in Japanese patients with exudative age-related macular degeneration and polypoidal choroidal vasculopathy. Am J Ophthalmol 147:1037–1041. https://doi.org/10.1016/j.ajo.2008.12.036. (1041.e1-2)

    Article  CAS  PubMed  Google Scholar 

  52. Hayashi H, Yamashiro K, Gotoh N, Nakanishi H, Nakata I, Tsujikawa A, Otani A, Saito M, Iida T, Matsuo K, Tajima K, Yamada R, Yoshimura N (2010) CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 51:5914–5919. https://doi.org/10.1167/iovs.10-5554

    Article  PubMed  Google Scholar 

  53. Fuse N, Mengkegale M, Miyazawa A, Abe T, Nakazawa T, Wakusawa R, Nishida K (2011) Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age-related macular degeneration. Am J Ophthalmol 151:550-556.e1. https://doi.org/10.1016/j.ajo.2010.08.048

    Article  CAS  PubMed  Google Scholar 

  54. Tanaka K, Nakayama T, Yuzawa M, Wang Z, Kawamura A, Mori R, Nakashizuka H, Sato N, Mizutani Y (2011) Analysis of candidate genes for age-related macular degeneration subtypes in the Japanese population. Mol Vis 17:2751–2758

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bessho H, Honda S, Kondo N, Negi A (2011) The association of ARMS2 polymorphisms with phenotype in typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Mol Vis 17:977–982

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Liang XY, Lai TY, Liu DT, Fan AH, Chen LJ, Tam PO, Chiang SW, Ng TK, Lam DS, Pang CP (2012) Differentiation of exudative age-related macular degeneration and polypoidal choroidal vasculopathy in the ARMS2/HTRA1 locus. Invest Ophthalmol Vis Sci 53:3175–3182. https://doi.org/10.1167/iovs.11-8135

    Article  CAS  PubMed  Google Scholar 

  57. Cheng Y, Huang L, Li X, Zhou P, Zeng W, Zhang C (2013) Genetic and functional dissection of ARMS2 in age-related macular degeneration and polypoidal choroidal vasculopathy. PLoS One 8:e53665. https://doi.org/10.1371/journal.pone.0053665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jiang JJ, Wu X, Zhou P, Yu WZ, Huang LZ, Li XX (2012) Meta-analysis of the relationship between the LOC387715/ARMS2 polymorphism and polypoidal choroidal vasculopathy. Genet Mol Res 11:4256–4267. https://doi.org/10.4238/2012.December.17.1

    Article  CAS  PubMed  Google Scholar 

  59. Lima LH, Schubert C, Ferrara DC, Merriam JE, Imamura Y, Freund KB, Spaide RF, Yannuzzi LA, Allikmets R (2010) Three major loci involved in age-related macular degeneration are also associated with polypoidal choroidal vasculopathy. Ophthalmology 117:1567–1570. https://doi.org/10.1016/j.ophtha.2009.12.018

    Article  PubMed  Google Scholar 

  60. Tanaka K, Nakayama T, Mori R, Sato N, Kawamura A, Mizutani Y, Yuzawa M (2011) Associations of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genotypes with subtypes of polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 52:7441–7444. https://doi.org/10.1167/iovs.11-7546

    Article  CAS  PubMed  Google Scholar 

  61. Miki A, Honda S, Kondo N, Negi A (2013) The association of age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) variants with two angiographic subtypes of polypoidal choroidal vasculopathy. Ophthalmic Genet 34:146–150. https://doi.org/10.3109/13816810.2012.749288

    Article  CAS  PubMed  Google Scholar 

  62. Miyake M, Ooto S, Yamashiro K, Takahashi A, Yoshikawa M, Akagi-Kurashige Y, Ueda-Arakawa N, Oishi A, Nakanishi H, Tamura H, Tsujikawa A, Yoshimura N (2015) Pachychoroid neovasculopathy and age-related macular degeneration. Sci Rep 5:16204. https://doi.org/10.1038/srep16204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yamashiro K, Hosoda Y, Miyake M, Ooto S, Tsujikawa A (2020) Characteristics of pachychoroid diseases and age-related macular degeneration: multimodal imaging and genetic backgrounds. J Clin Med 9:2034. https://doi.org/10.3390/jcm9072034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Thee EF, Colijn JM, Cougnard-Grégoire A, Meester-Smoor MA, Verzijden T, Hoyng CB, Fauser S, Hense HW, Silva R, Creuzot-Garcher C, Ueffing M, Delcourt C, den Hollander AI, Klaver CCW; European Eye Epidemiology Consortium and EYE-RISK Project (2022) The phenotypic course of age-related macular degeneration for ARMS2/HTRA1: the EYE-RISK consortium. Ophthalmology 129:752–764. https://doi.org/10.1016/j.ophtha.2022.02.026

    Article  Google Scholar 

  65. Chen W, Xu W, Tao Q, Liu J, Li X, Gan X, Hu H, Lu Y (2009) Meta-analysis of the association of the HTRA1 polymorphisms with the risk of age-related macular degeneration. Exp Eye Res 89:292–300. https://doi.org/10.1016/j.exer.2008.10.017

    Article  CAS  PubMed  Google Scholar 

  66. Mori Y, Miyake M, Hosoda Y, Miki A, Takahashi A, Muraoka Y, Miyata M, Sato T, Tamura H, Ooto S, Yamada R, Yamashiro K, Nakamura M, Tajima A, Nagasaki M, Honda S, Tsujikawa A (2022) Genome-wide survival analysis for macular neovascularization development in central serous chorioretinopathy revealed shared genetic susceptibility with polypoidal choroidal vasculopathy. Ophthalmology 129:1034–1042. https://doi.org/10.1016/j.ophtha.2022.04.018

    Article  PubMed  Google Scholar 

  67. Hosoda Y, Yamashiro K, Miyake M, Ooto S, Oishi A, Miyata M, Uji A, Khor CC, Wong TY, Tsujikawa A (2019) Predictive genes for the prognosis of central serous chorioretinopathy. Ophthalmol Retina 3:985–992. https://doi.org/10.1016/j.oret.2019.05.025

    Article  PubMed  Google Scholar 

  68. Cho SC, Ryoo NK, Ahn J, Woo SJ, Park KH (2020) Association of irregular pigment epithelial detachment in central serous chorioretinopathy with genetic variants implicated in age-related macular degeneration. Sci Rep 10:1203. https://doi.org/10.1038/s41598-020-57747-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sakurada Y, Kubota T, Imasawa M, Tsumura T, Mabuchi F, Tanabe N, Iijima H (2009) Angiographic lesion size associated with LOC387715 A69S genotype in subfoveal polypoidal choroidal vasculopathy. Retina 29:1522–1526. https://doi.org/10.1097/IAE.0b013e3181af0d72

    Article  PubMed  Google Scholar 

  70. Yoneyama S, Sakurada Y, Kikushima W, Sugiyama A, Tanabe N, Mabuchi F, Kubota T, Iijima H (2016) Genetic factors associated with choroidal vascular hyperpermeability and subfoveal choroidal thickness in polypoidal choroidal vasculopathy. Retina 36:1535–1541. https://doi.org/10.1097/IAE.0000000000000964

    Article  PubMed  Google Scholar 

  71. Ryoo NK, Ahn SJ, Park KH, Ahn J, Seo J, Han JW, Kim KW, Woo SJ (2018) Thickness of retina and choroid in the elderly population and its association with Complement Factor H polymorphism: KLoSHA Eye study. PLoS One 13:e0209276. https://doi.org/10.1371/journal.pone.0209276

    Article  PubMed  PubMed Central  Google Scholar 

  72. Fenner BJ, Li H, Gan ATL, Song YS, Tham YC, Jonas JB, Wang YX, Cheng CY, Wong TY, Teo KYC, Tan ACS, Fan Q, Cheung CMG (2023) Genetic variability of complement factor H has ethnicity-specific associations with choroidal thickness. Invest Ophthalmol Vis Sci 64:10. https://doi.org/10.1167/iovs.64.2.10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41:355–367. https://doi.org/10.1016/j.molimm.2004.02.005

    Article  CAS  PubMed  Google Scholar 

  74. Ormsby RJ, Jokiranta TS, Duthy TG, Griggs KM, Sadlon TA, Giannakis E, Gordon DL (2006) Localization of the third heparin-binding site in the human complement regulator factor H1. Mol Immunol 43:1624–1632. https://doi.org/10.1016/j.molimm.2005.09.012

    Article  CAS  PubMed  Google Scholar 

  75. Schönauer R, Seidel A, Grohmann M, Lindner TH, Bergmann C, Halbritter J (2019) Deleterious impact of a novel CFH splice site variant in atypical hemolytic uremic syndrome. Front Genet 10:465. https://doi.org/10.3389/fgene.2019.00465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wu J, Wu YQ, Ricklin D, Janssen BJ, Lambris JD, Gros P (2009) Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat Immunol 10:728–733. https://doi.org/10.1038/ni.1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hocking HG, Herbert AP, Kavanagh D, Soares DC, Ferreira VP, Pangburn MK, Uhrín D, Barlow PN (2008) Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations. J Biol Chem 283:9475–9487. https://doi.org/10.1074/jbc.M709587200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Okemefuna AI, Nan R, Miller A, Gor J, Perkins SJ (2010) Complement factor H binds at two independent sites to C-reactive protein in acute phase concentrations. J Biol Chem 285:1053–1065. https://doi.org/10.1074/jbc.M109.044529

    Article  CAS  PubMed  Google Scholar 

  79. Giannakis E, Male DA, Ormsby RJ, Mold C, Jokiranta TS, Ranganathan S, Gordon DL (2001) Multiple ligand binding sites on domain seven of human complement factor H. Int Immunopharmacol 1:433–443. https://doi.org/10.1016/s1567-5769(00)00040-0

    Article  CAS  PubMed  Google Scholar 

  80. Ormsby RJ, Ranganathan S, Tong JC, Griggs KM, Dimasi DP, Hewitt AW, Burdon KP, Craig JE, Hoh J, Gordon DL (2008) Functional and structural implications of the complement factor H Y402H polymorphism associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 49:1763–1770. https://doi.org/10.1167/iovs.07-1297

    Article  PubMed  Google Scholar 

  81. Molins B, Fuentes-Prior P, Adán A, Antón R, Arostegui JI, Yagüe J, Dick AD (2016) Complement factor H binding of monomeric C-reactive protein downregulates proinflammatory activity and is impaired with at risk polymorphic CFH variants. Sci Rep 6:22889. https://doi.org/10.1038/srep22889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Perkins SJ, Nan R, Li K, Khan S, Miller A (2012) Complement factor H-ligand interactions: self-association, multivalency and dissociation constants. Immunobiology 217:281–297. https://doi.org/10.1016/j.imbio.2011.10.003

    Article  CAS  PubMed  Google Scholar 

  83. Johnson PT, Betts KE, Radeke MJ, Hageman GS, Anderson DH, Johnson LV (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 U S A 103:17456–17461. https://doi.org/10.1073/pnas.0606234103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ufret-Vincenty RL, Aredo B, Liu X, McMahon A, Chen PW, Sun H, Niederkorn JY, Kedzierski W (2010) Transgenic mice expressing variants of complement factor H develop AMD-like retinal findings. Invest Ophthalmol Vis Sci 51:5878–5887. https://doi.org/10.1167/iovs.09-4457

    Article  PubMed  Google Scholar 

  85. Radu RA, Hu J, Jiang Z, Bok D (2014) Bisretinoid-mediated complement activation on retinal pigment epithelial cells is dependent on complement factor H haplotype. J Biol Chem 289:9113–9120. https://doi.org/10.1074/jbc.M114.548669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sim RB, Ferluga J, Al-Rashidi H, Abbow H, Schwaeble W, Kishore U (2015) Complement factor H in its alternative identity as adrenomedullin-binding protein 1. Mol Immunol 68:45–48. https://doi.org/10.1016/j.molimm.2015.06.006

    Article  CAS  PubMed  Google Scholar 

  87. Dorner GT, Garhöfer G, Huemer KH, Golestani E, Zawinka C, Schmetterer L, Wolzt M (2003) Effects of adrenomedullin on ocular hemodynamic parameters in the choroid and the ophthalmic artery. Invest Ophthalmol Vis Sci 44:3947–3951. https://doi.org/10.1167/iovs.02-0855

    Article  PubMed  Google Scholar 

  88. Yan F, Gao M, Gong Y, Zhang L, Ai N, Zhang J, Chai Y, Wu S, Liu Q, Jiang X, Deng H, Liu W (2020) Proteomic analysis of underlying apoptosis mechanisms of human retinal pigment epithelial ARPE-19 cells in response to mechanical stretch. J Cell Physiol 235:7604–7619. https://doi.org/10.1002/jcp.29670

    Article  CAS  PubMed  Google Scholar 

  89. Hou X, Han QH, Hu D, Tian L, Guo CM, Du HJ, Zhang P, Wang YS, Hui YN (2009) Mechanical force enhances MMP-2 activation via p38 signaling pathway in human retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol 247:1477–1486. https://doi.org/10.1007/s00417-009-1135-1

    Article  CAS  PubMed  Google Scholar 

  90. Seko Y, Seko Y, Fujikura H, Pang J, Tokoro T, Shimokawa H (1999) Induction of vascular endothelial growth factor after application of mechanical stress to retinal pigment epithelium of the rat in vitro. Invest Ophthalmol Vis Sci 40:3287–3291

    CAS  PubMed  Google Scholar 

  91. García-Ponce A, Chánez Paredes S, Castro Ochoa KF, Schnoor M (2016) Regulation of endothelial and epithelial barrier functions by peptide hormones of the adrenomedullin family. Tissue Barriers 4:e1228439. https://doi.org/10.1080/21688370.2016.1228439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Martínez A, Oh HR, Unsworth EJ, Bregonzio C, Saavedra JM, Stetler-Stevenson WG, Cuttitta F (2004) Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator. Biochem J 383:413–418. https://doi.org/10.1042/BJ20040920

    Article  PubMed  PubMed Central  Google Scholar 

  93. Pio R, Martinez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, Elsasser TH, Cuttitta F (2001) Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 276:12292–12300. https://doi.org/10.1074/jbc.M007822200

    Article  CAS  PubMed  Google Scholar 

  94. Tunyasuvunakool K, Adler J, Wu Z et al (2021) Highly accurate protein structure prediction for the human proteome. Nature 596:590–596. https://doi.org/10.1038/s41586-021-03828-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schmidt CQ, Herbert AP, Kavanagh D, Gandy C, Fenton CJ, Blaum BS, Lyon M, Uhrín D, Barlow PN (2008) A new map of glycosaminoglycan and C3b binding sites on factor H. J Immunol 181:2610–2619. https://doi.org/10.4049/jimmunol.181.4.2610

    Article  CAS  PubMed  Google Scholar 

  96. Kortvely E, Hauck SM, Duetsch G, Gloeckner CJ, Kremmer E, Alge-Priglinger CS, Deeg CA, Ueffing M (2010) ARMS2 is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degenerations. Invest Ophthalmol Vis Sci 51:79–88. https://doi.org/10.1167/iovs.09-3850

    Article  PubMed  Google Scholar 

  97. Micklisch S, Lin Y, Jacob S, Karlstetter M, Dannhausen K, Dasari P, von der Heide M, Dahse HM, Schmölz L, Grassmann F, Alene M, Fauser S, Neumann H, Lorkowski S, Pauly D, Weber BH, Joussen AM, Langmann T, Zipfel PF, Skerka C (2017) Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator. J Neuroinflammation 14:4. https://doi.org/10.1186/s12974-016-0776-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A (2007) A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A 104:16227–16232. https://doi.org/10.1073/pnas.0703933104

    Article  PubMed  PubMed Central  Google Scholar 

  99. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, Weber BH (2008) Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 40:89289–89296. https://doi.org/10.1038/ng.170

    Article  CAS  Google Scholar 

  100. 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. https://doi.org/10.1086/444437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang G, Spencer KL, Scott WK, Whitehead P, Court BL, Ayala-Haedo J, Mayo P, Schwartz SG, Kovach JL, Gallins P, Polk M, Agarwal A, Postel EA, Haines JL, Pericak-Vance MA (2010) Analysis of the indel at the ARMS2 3’UTR in age-related macular degeneration. Hum Genet 127:595–602. https://doi.org/10.1007/s00439-010-0805-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liao SM, Zheng W, Zhu J, Lewis CA, Delgado O, Crowley MA, Buchanan NM, Jaffee BD, Dryja TP (2017) Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of HTRA1. Mol Vis 23:318–333

    PubMed  PubMed Central  Google Scholar 

  103. Nakayama M, Iejima D, Akahori M, Kamei J, Goto A, Iwata T (2014) Overexpression of HtrA1 and exposure to mainstream cigarette smoke leads to choroidal neovascularization and subretinal deposits in aged mice. Invest Ophthalmol Vis Sci 55:6514–6523. https://doi.org/10.1167/iovs.14-14453

    Article  CAS  PubMed  Google Scholar 

  104. Jones A, Kumar S, Zhang N, Tong Z, Yang JH, Watt C, Anderson J, Amrita FH, McCloskey M, Luo L, Yang Z, Ambati B, Marc R, Oka C, Zhang K, Fu Y (2011) Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc Natl Acad Sci U S A 108:14578–14583. https://doi.org/10.1073/pnas.1102853108

    Article  PubMed  PubMed Central  Google Scholar 

  105. Vierkotten S, Muether PS, Fauser S (2011) Overexpression of HTRA1 leads to ultrastructural changes in the elastic layer of Bruch’s membrane via cleavage of extracellular matrix components. PLoS One 6:e22959. https://doi.org/10.1371/journal.pone.0022959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lin MK, Yang J, Hsu CW, Gore A, Bassuk AG, Brown LM, Colligan R, Sengillo JD, Mahajan VB, Tsang SH (2018) HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1. Aging Cell 17:e12710. https://doi.org/10.1111/acel.12710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen CY, Melo E, Jakob P, Friedlein A, Elsässer B, Goettig P, Kueppers V, Delobel F, Stucki C, Dunkley T, Fauser S, Schilling O, Iacone R (2018) N-Terminomics identifies HtrA1 cleavage of thrombospondin-1 with generation of a proangiogenic fragment in the polarized retinal pigment epithelial cell model of age-related macular degeneration. Matrix Biol 70:84–101. https://doi.org/10.1016/j.matbio.2018.03.013

    Article  CAS  PubMed  Google Scholar 

  108. Kumar S, Nakashizuka H, Jones A, Lambert A, Zhao X, Shen M, Parker M, Wang S, Berriochoa Z, Fnu A, VanBeuge S, Chévez-Barrios P, Tso M, Rainier J, Fu Y (2017) Proteolytic degradation and inflammation play critical roles in polypoidal choroidal vasculopathy. Am J Pathol 187:2841–2857. https://doi.org/10.1016/j.ajpath.2017.08.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML (2007) Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 297:1793–1800. https://doi.org/10.1001/jama.297.16.1793

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported in part by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT)—No. 22 K09773. The funding organizations had no role in the design or conduct of this research.

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Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, Japan

    Shigeru Honda & Norihiko Misawa

  2. Center for Research On Green Sustainable Chemistry, Graduate School of Engineering, Tottori University, Tottori, Japan

    Yusuke Sato

  3. Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori, Japan

    Yusuke Sato

  4. Department of Medical Biochemistry, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan

    Daisuke Oikawa & Fuminori Tokunaga

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  1. Shigeru Honda
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Honda, S., Misawa, N., Sato, Y. et al. The hypothetical molecular mechanism of the ethnic variations in the manifestation of age-related macular degeneration; focuses on the functions of the most significant susceptibility genes. Graefes Arch Clin Exp Ophthalmol (2024). https://doi.org/10.1007/s00417-024-06442-9

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