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Investigation of genetic base in the treatment of age-related macular degeneration

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Abstract

Purpose

To determine whether gene polymorphisms which are associated with age-related macular degeneration (AMD) influence treatments’ response and specifically the antioxidant supplementation in dry AMD patients, as well as the anti-vascular endothelial growth factor (anti-VEGF) therapy in neovascular AMD patients.

Methods

A total of 170 patients with dry AMD and 52 neovascular AMD patients were genotyped for the following single nucleotide polymorphisms (SNPs): rs1061170/Y402H in CFH gene, rs10490924/A69S in ARMS2 gene, rs9332739/E318D and rs547154/IVS10 in C2 gene, and rs4151667/L9H and rs2072633/IVS17 in CFB gene. Treatment response was evaluated by comparing visual acuity and optical coherence tomography between baseline and at the end of the treatment.

Results

Τhe CFH/Y402H variant was associated with the response to antioxidants in dry AMD patients. Carriers of one or two CFH risk alleles displayed a lower chance of responding compared to those with no risk allele. No association of antioxidants’ response and ARMS2/A69S genotype was identified. The analysis of the C2 and CFB genetic variants (protective SNPs) revealed that antioxidant supplementation was much more effective in protective SNP carriers. In neovascular AMD patients, the analysis indicated that Y402H homozygous patients were less likely to respond to anti-VEGF therapy compared to heterozygous. Regarding the ARMS2/A69S genotype, carriers of the risk variant experienced significantly worse treatment outcome compared to wild-type patients.

Conclusion

In AMD patients, the efficacy of the antioxidant supplementation and the anti-VEGF therapy appears to differ by genotype. The detection of genetic variants, associated with treatment responsiveness, could lead to improved visual outcomes through genotype-directed therapy.

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References

  1. Bourne RR, Jonas JB, Flaxman SR, Keeffe J, Leasher J, Naidoo K, Parodi MB, Pesudovs K, Price H, White RA, Wong TY, Resnikoff S, Taylor HR, Vision Loss Expert Group of the Global Burden of Disease S (2014) Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990–2010. Br J Ophthalmol 98(5):629–638. https://doi.org/10.1136/bjophthalmol-2013-304033

    Article  PubMed  Google Scholar 

  2. Jager RD, Mieler WF, Miller JW (2008) Age-related macular degeneration. N Engl J Med 358(24):2606–2617. https://doi.org/10.1056/NEJMra0801537

    Article  CAS  PubMed  Google Scholar 

  3. Grisanti S, Tatar O (2008) The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration. Prog Retin Eye Res 27(4):372–390. https://doi.org/10.1016/j.preteyeres.2008.05.002

    Article  CAS  PubMed  Google Scholar 

  4. Age-Related Eye Disease Study Research G (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(10):1417–1436

    Article  Google Scholar 

  5. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, Group AS (2009) Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 116(1):57–65. https://doi.org/10.1016/j.ophtha.2008.10.018

    Article  PubMed  Google Scholar 

  6. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, Group MS (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355(14):1419–1431. https://doi.org/10.1056/NEJMoa054481

    Article  CAS  PubMed  Google Scholar 

  7. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY (2012) Age-related macular degeneration. Lancet 379(9827):1728–1738. https://doi.org/10.1016/S0140-6736(12)60282-7

    Article  PubMed  Google Scholar 

  8. Al-Zamil WM, Yassin SA (2017) Recent developments in age-related macular degeneration: a review. Clin Interv Aging 12:1313–1330. https://doi.org/10.2147/CIA.S143508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Seddon JM, Ajani UA, Mitchell BD (1997) Familial aggregation of age-related maculopathy. Am J Ophthalmol 123(2):199–206

    Article  CAS  Google Scholar 

  10. 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. https://doi.org/10.1001/archopht.123.3.321

    Article  PubMed  Google Scholar 

  11. 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(4):730–736

    Article  Google Scholar 

  12. 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(16):1793–1800. https://doi.org/10.1001/jama.297.16.1793

    Article  CAS  PubMed  Google Scholar 

  13. Shuler RK Jr, Hauser MA, Caldwell J, Gallins P, Schmidt S, Scott WK, Agarwal A, Haines JL, Pericak-Vance MA, Postel EA (2007) Neovascular age-related macular degeneration and its association with LOC387715 and complement factor H polymorphism. Arch Ophthalmol 125(1):63–67. https://doi.org/10.1001/archopht.125.1.63

    Article  CAS  PubMed  Google Scholar 

  14. 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(5720):421–424. https://doi.org/10.1126/science.1110189

    Article  CAS  PubMed  Google Scholar 

  15. 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(5720):385–389. https://doi.org/10.1126/science.1109557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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(5720):419–421. https://doi.org/10.1126/science.1110359

    Article  CAS  PubMed  Google Scholar 

  17. 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(21):3227–3236. https://doi.org/10.1093/hmg/ddi353

    Article  CAS  PubMed  Google Scholar 

  18. 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 USA 104(41):16227–16232. https://doi.org/10.1073/pnas.0703933104

    Article  PubMed  Google Scholar 

  19. Andreoli MT, Morrison MA, Kim BJ, Chen L, Adams SM, Miller JW, DeAngelis MM, Kim IK (2009) Comprehensive analysis of complement factor H and LOC387715/ARMS2/HTRA1 variants with respect to phenotype in advanced age-related macular degeneration. Am J Ophthalmol 148(6):869–874. https://doi.org/10.1016/j.ajo.2009.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brantley MA Jr, Fang AM, King JM, Tewari A, Kymes SM, Shiels A (2007) Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 114(12):2168–2173. https://doi.org/10.1016/j.ophtha.2007.09.008

    Article  PubMed  Google Scholar 

  21. Awh CC, Lane AM, Hawken S, Zanke B, Kim IK (2013) CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology 120(11):2317–2323. https://doi.org/10.1016/j.ophtha.2013.07.039

    Article  PubMed  Google Scholar 

  22. Bardak H, Bardak Y, Ercalik Y, Turkseven Kumral E, Imamoglu S, Gunay M, Ozbas H, Bagci O (2016) Effect of ARMS2 gene polymorphism on intravitreal ranibizumab treatment for neovascular age-related macular degeneration. Genet Mol Res. https://doi.org/10.4238/gmr15049164

    Article  PubMed  Google Scholar 

  23. Seddon JM, Silver RE, Rosner B (2016) Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol 100(12):1731–1737. https://doi.org/10.1136/bjophthalmol-2016-308624

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chaudhary V, Brent M, Lam WC, Devenyi R, Teichman J, Mak M, Barbosa J, Kaur H, Carter R, Farrokhyar F (2016) Genetic risk evaluation in wet age-related macular degeneration treatment response. Ophthalmol J Int 236(2):88–94. https://doi.org/10.1159/000446819

    Article  CAS  Google Scholar 

  25. Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL (2007) Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet 16(16):1986–1992. https://doi.org/10.1093/hmg/ddm146

    Article  CAS  PubMed  Google Scholar 

  26. 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(9):1055–1059. https://doi.org/10.1038/ng1873

    Article  CAS  PubMed  Google Scholar 

  27. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, Group AMDGCS, Hageman GS, Dean M, Allikmets R (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. https://doi.org/10.1038/ng1750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Francis PJ, Hamon SC, Ott J, Weleber RG, Klein ML (2009) Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet 46(5):300–307. https://doi.org/10.1136/jmg.2008.062737

    Article  CAS  PubMed  Google Scholar 

  29. Campbell I (2007) Chi squared and Fisher-Irwin tests of two-by-two tables with small sample recommendations. Stat Med 26(19):3661–3675. https://doi.org/10.1002/sim.2832

    Article  PubMed  Google Scholar 

  30. Age-Related Eye Disease Study 2 Research G (2013) Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 309(19):2005–2015. https://doi.org/10.1001/jama.2013.4997

    Article  CAS  Google Scholar 

  31. Gorin MB (2012) Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics. Mol Aspects Med 33(4):467–486. https://doi.org/10.1016/j.mam.2012.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Garcia M, Alvarez L, Nogacka AM, Gonzalez-Iglesias H, Escribano J, Fernandez-Vega B, Fernandez-Vega A, Fernandez-Vega L, Coca-Prados M (2015) CFH polymorphisms in a Northern Spanish population with neovascular and dry forms of age-related macular degeneration. Acta Ophthalmol 93(8):e658–e666. https://doi.org/10.1111/aos.12790

    Article  CAS  PubMed  Google Scholar 

  33. Leveziel N, Puche N, Richard F, Somner JE, Zerbib J, Bastuji-Garin S, Cohen SY, Korobelnik JF, Sahel J, Soubrane G, Benlian P, Souied EH (2010) Genotypic influences on severity of exudative age-related macular degeneration. Invest Ophthalmol Vis Sci 51(5):2620–2625. https://doi.org/10.1167/iovs.09-4423

    Article  PubMed  Google Scholar 

  34. Klein ML, Francis PJ, Rosner B, Reynolds R, Hamon SC, Schultz DW, Ott J, Seddon JM (2008) CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 115(6):1019–1025. https://doi.org/10.1016/j.ophtha.2008.01.036

    Article  PubMed  Google Scholar 

  35. Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr (2009) Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 93(5):610–613. https://doi.org/10.1136/bjo.2008.150995

    Article  CAS  PubMed  Google Scholar 

  36. Dedania VS, Grob S, Zhang K, Bakri SJ (2015) Pharmacogenomics of response to anti-VEGF therapy in exudative age-related macular degeneration. Retina 35(3):381–391. https://doi.org/10.1097/IAE.0000000000000466

    Article  CAS  PubMed  Google Scholar 

  37. Awh CC, Hawken S, Zanke BW (2015) Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology 122(1):162–169. https://doi.org/10.1016/j.ophtha.2014.07.049

    Article  PubMed  Google Scholar 

  38. Chew EY, Klein ML, Clemons TE, Agron E, Ratnapriya R, Edwards AO, Fritsche LG, Swaroop A, Abecasis GR, Age-Related Eye Disease Study Research G (2014) No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology 121(11):2173–2180. https://doi.org/10.1016/j.ophtha.2014.05.008

    Article  PubMed  PubMed Central  Google Scholar 

  39. Assel MJ, Li F, Wang Y, Allen AS, Baggerly KA, Vickers AJ (2018) Genetic polymorphisms of CFH and ARMS2 do not predict response to antioxidants and zinc in patients with age-related macular degeneration: independent statistical evaluations of data from the Age-Related Eye Disease Study. Ophthalmology 125(3):391–397. https://doi.org/10.1016/j.ophtha.2017.09.008

    Article  PubMed  Google Scholar 

  40. Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, Michels S, Fleischhauer J, Berger W, Sutter F, Menghini M (2011) Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD. Invest Ophthalmol Vis Sci 52(7):4694–4702. https://doi.org/10.1167/iovs.10-6080

    Article  CAS  PubMed  Google Scholar 

  41. Orlin A, Hadley D, Chang W, Ho AC, Brown G, Kaiser RS, Regillo CD, Godshalk AN, Lier A, Kaderli B, Stambolian D (2012) Association between high-risk disease loci and response to anti-vascular endothelial growth factor treatment for wet age-related macular degeneration. Retina 32(1):4–9. https://doi.org/10.1097/IAE.0b013e31822a2c7c

    Article  CAS  PubMed  Google Scholar 

  42. Teper SJ, Nowinska A, Pilat J, Palucha A, Wylegala E (2010) Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration. Mol Vis 16:2598–2604

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kitchens JW, Kassem N, Wood W, Stone TW, Isernhagen R, Wood E, Hancock BA, Radovich M, Waymire J, Li L, Schneider BP (2013) A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration. Clin Ophthalmol 7:1987–1993. https://doi.org/10.2147/OPTH.S39635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kaur I, Katta S, Reddy RK, Narayanan R, Mathai A, Majji AB, Chakrabarti S (2010) The involvement of complement factor B and complement component C2 in an Indian cohort with age-related macular degeneration. Invest Ophthalmol Vis Sci 51(1):59–63. https://doi.org/10.1167/iovs.09-4135

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Genetics and Biotechnology, Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Ilissia, 15701, Athens, Greece

    Kalliopi Gourgouli & Klea Lamnissou

  2. Department of Ophthalmology, Sismanoglio General Hospital of Attica, Athens, Greece

    Ioanna Gourgouli & Sofia Spai

  3. Division of Cell Biology and Biophysics, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece

    Georgios Tsaousis

  4. Consultant Ophthalmic Surgeon, Agias Paraskevis 118, Chalandri, 15232, Athens, Greece

    Maria Niskopoulou

  5. Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece

    Spiros Efthimiopoulos

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  1. Kalliopi Gourgouli
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All procedures performed in these patients were in accordance with the Ethics Code of the National and Kapodistrian University of Athens (NKUA) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Gourgouli, K., Gourgouli, I., Tsaousis, G. et al. Investigation of genetic base in the treatment of age-related macular degeneration. Int Ophthalmol 40, 985–997 (2020). https://doi.org/10.1007/s10792-019-01274-7

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