Genetic Variants of Complement Factor H Y402H (rs1061170), C2 R102G (rs2230199), and C3 E318D (rs9332739) and Response to Intravitreal Anti-VEGF Treatment in Patients with Exudative Age-Related Macular Degeneration
Abstract
:1. Introduction
2. Materials and Methods
2.1. Genotyping
2.1.1. Genomic DNA Isolation
2.1.2. Genotyping of Single Nucleotide Polymorphisms
2.2. Statistical Analysis
3. Results
3.1. Characteristics of Patients and Controls
3.2. Genotype and Allele Frequencies of Polymorphisms in Complement System Genes
3.3. Associations between Polymorphisms of Complement System Genes and Response to Anti-VEGF Therapy
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Bourne, R.R.; Jonas, J.B.; Flaxman, S.R.; Keeffe, J.; Leasher, J.; Naidoo, K.; Parodi, M.B.; Pesudovs, K.; Price, H.; White, R.A.; et al. Vision Loss Expert Group of the Global Burden of Disease Study. Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990–2010. Br. J. Ophthalmol. 2014, 98, 629–638. [Google Scholar] [CrossRef]
- Rein, D.B.; Wittenborn, J.S.; Zhang, X.; Honeycutt, A.A.; Lesesne, S.B.; Saaddine, J.; Vision Health Cost-Effectiveness Study Group. Forecasting age-related macular degeneration through the year 2050: The potential impact of new treatments. Arch. Ophthalmol. 2009, 127, 533–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wong, W.L.; Su, X.; Li, X.; Cheung, C.M.G.; Klein, R.; Cheng, C.Y.; Wong, T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e106–e116. [Google Scholar] [CrossRef] [Green Version]
- Smith, W.; Assink, J.; Klein, R.; Mitchell, P.; Klaver, C.C.; Klein, B.E.; Hofman, A.; Jensen, S.; Wang, J.J.; de Jong, P.T. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001, 108, 697–704. [Google Scholar] [CrossRef]
- Velilla, S.; García-Medina, J.J.; García-Layana, A.; Dolz-Marco, R.; Pons-Vazquez, S.; Pinazo-Duran, M.D.; Gomez-Ulla, F.; Arevalo, J.F.; Diaz-Llopis, M.; Gallego-Pinazo, R. Smoking and age-related macular degeneration: Review and update. J. Ophthalmol. 2013, 2013, 895147. [Google Scholar] [CrossRef] [PubMed]
- Deng, Y.; Qiao, L.; Du, M.; Qu, C.; Wan, L.; Li, J.; Huang, L. Age-related macular degeneration: Epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy. Genes Dis. 2022, 9, 62–79. [Google Scholar] [CrossRef]
- Cascella, R.; Ragazzo, M.; Strafella, C.; Missiroli, F.; Borgiani, P.; Angelucci, F.; Marsella, L.T.; Cusumano, A.; Novelli, G.; Ricci, F.; et al. Age-related macular degeneration: Insights into inflammatory genes. J. Ophthalmol. 2014, 2014, 582842–582846. [Google Scholar] [CrossRef]
- Kubicka-Trzaska, A.; Zuber-Laskawiec, K.; Plutecka, H.; Romanowska-Dixon, B.; Sanak, M.; Karska-Basta, I. Altered serum levels of autophagy proteins Beclin-1 and mTOR in patients with exudative age-related macular degeneration. J. Physiol. Pharmacol. 2021, 72, 89–95. [Google Scholar] [CrossRef]
- Kubicka-Trzaska, A.; Karska-Basta, I.; Żuber-Łaskawiec, K. Autophagy: A new insight into pathogenesis and treatment possibilities in age-related macular degeneration. Postepy Hig. I Med. Dosw. 2020, 74, 213–223. [Google Scholar] [CrossRef]
- Tan, W.; Zou, J.; Yoshida, S.; Jiang, B.; Zhou, Y. The role of inflammation in age-related macular degeneration. Int. J. Biol. Sci. 2020, 16, 2989–3001. [Google Scholar] [CrossRef]
- Fleckenstein, M.; Keenan, T.D.L.; Guymer, R.H.; Chakravarthy, U.; Schmitz-Valckenberg, S.; Klaver, C.C.; Wong, W.T.; Chew, E.Y. Age-related macular degeneration. Nat. Rev. Dis. Primers 2021, 7, 31. [Google Scholar] [CrossRef] [PubMed]
- DeAngelis, M.M.; Owen, L.A.; Morrison, M.A.; Morgan, D.J.; Li, M.; Shakoor, A.; Vitale, A.; Iyengar, S.; Stambolian, D.; Kim, I.K.; et al. Genetics of age-related macular degeneration (AMD). Hum. Mol. Genet. 2017, 26, R45–R50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Warwick, A.; Lotery, A. Genetics and genetic testing for age-related macular degeneration. Eye 2018, 32, 849–857. [Google Scholar] [CrossRef] [PubMed]
- Haddad, S.; Chen, C.A.; Santangelo, S.L.; Seddon, J.M. The genetics of age-related macular degeneration: A review of progress to date. Surv. Ophthalmol. 2006, 51, 316–363. [Google Scholar] [CrossRef] [PubMed]
- Grassmann, F.; Heid, I.M.; Weber, B.H.; International AMD Genomics Consortium (IAMDGC). Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration. Genetics 2017, 205, 919–924. [Google Scholar] [CrossRef] [PubMed]
- Ricklin, D.; Hajishengallis, G.; Yang, K.; Lambris, J.D. Complement: A key system for immune surveillance and homeostasis. Nat. Immunol. 2010, 11, 785–797. [Google Scholar] [CrossRef] [Green Version]
- McHarg, S.; Clark, S.J.; Day, A.J.; Bishop, P.N. Age-related macular degeneration and the role of the complement system. Mol. Immunol. 2015, 67, 43–50. [Google Scholar] [CrossRef]
- Whitmore, S.S.; Sohn, E.H.; Chirco, K.R.; Drack, A.V.; Stone, E.M.; Tucker, B.A.; Mullins, R.F. Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy. Prog. Retin. Eye Res. 2015, 45, 1–29. [Google Scholar] [CrossRef] [Green Version]
- Dunkelberger, J.; Song, W.C. Complement and its role in innate and adaptive immune responses. Cell Res. 2009, 20, 34–50. [Google Scholar] [CrossRef] [Green Version]
- Klein, R.J.; Zeiss, C.; Chew, E.Y.; Tsai, J.Y.; Sackler, R.S.; Haynes, C.; Henning, A.K.; SanGiovanni, J.P.; Mane, S.M.; Mayne, S.T.; et al. Complement factor h polymorphism in age-related macular degeneration. Science 2005, 308, 385–389. [Google Scholar] [CrossRef]
- Fritsche, L.G.; Chen, W.; Schu, M.; Yaspan, B.L.; Yu, Y.; Thorleifsson, G.; Zack, D.J.; Arakawa, S.; Cipriani, V.; Ripke, S.; et al. Seven new loci associated with age-related macular degeneration. Nat. Genet. 2013, 45, 433–439. [Google Scholar] [CrossRef] [PubMed]
- Black, J.R.M.; Clark, S.J. Age-related macular degeneration: Genome-wide association studies to translation. Genet. Med. 2016, 18, 283–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Armento, A.; Ueffing, M.; Clark, S.J. The complement system in age-related macular degeneration. Cell. Mol. Life Sci. 2021, 78, 4487–4505. [Google Scholar] [CrossRef] [PubMed]
- Fritsche, L.G.; Igl, W.; Bailey, J.N.C.; Grassmann, F.; Sengupta, S.; Bragg-Gresham, J.L.; Burdon, K.P.; Hebbring, S.J.; Wen, C.; Gorski, M.; et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat. Genet. 2016, 48, 134–143. [Google Scholar] [CrossRef] [Green Version]
- Wegscheider, B.J.; Weger, M.; Renner, W.; Steinbrugger, I.; März, W.; Mossböck, G.; Temmel, W.; El-Shabrawi, Y.; Schmut, O.; Jahrbacher, R.; et al. Association of complement factor h y402h gene polymorphism with different subtypes of exudative age-related macular degeneration. Ophthalmology 2007, 114, 738–742. [Google Scholar] [CrossRef] [PubMed]
- Borras, C.; Canonica, J.; Jorieux, S.; Abache, T.; El Sanharawi, M.; Klein, C.; Delaunay, K.; Jonet, L.; Salvodelli, M.; Naud, M.C.; et al. CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex. Sci. Rep. 2019, 9, 13873. [Google Scholar] [CrossRef] [Green Version]
- Wu, M.; Guo, Y.; Ma, Y.; Zheng, Z.; Wang, Q.; Zhou, X. Association of two polymorphisms, rs1061170 and rs1410996, in complement factor h with age-related macular degeneration in an Asian population: A meta-analysis. Ophthalmic Res. 2016, 55, 135–144. [Google Scholar] [CrossRef]
- Su, Y.; Hu, Z.; Pan, T.; Chen, L.; Xie, P.; Liu, Q. Complement factor B gene polymorphisms and risk of age-related macular degeneration: A meta-analysis. Eur. J. Ophthalmol. 2020, 30, 743–755. [Google Scholar] [CrossRef]
- Marioli, D.I.; Pharmakakis, N.; Deli, A.; Havvas, I.; Zarkadis, I.K. Complement factor H and LOC387715 gene polymorphisms in a Greek population with age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 2009, 247, 1547–1553. [Google Scholar] [CrossRef]
- Lu, F.; Liu, S.; Hao, Q.; Liu, L.; Zhang, J.; Chen, X.; Hu, W.; Huang, P. Association between complement factor C2/C3/CFB/CFH polymorphisms and age-related macular degeneration: A meta-analysis. Genet. Test. Mol. Biomark. 2018, 22, 526–540. [Google Scholar] [CrossRef]
- Brantley, M.A., Jr.; Fang, A.M.; King, J.M.; Tewari, A.; Kymes, S.M.; Shiels, A. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology 2007, 114, 2168–2173. [Google Scholar] [CrossRef] [PubMed]
- Kloeckener-Gruissem, B.; Barthelmes, D.; Labs, S.; Schindler, C.; Kurz-Levin, M.; Michels, S.; Fleischhauer, J.; Berger, W.; Sutter, F.; Menghini, M. Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD. Investig. Ophthalmol. Vis. Sci. 2011, 52, 4694–4702. [Google Scholar] [CrossRef] [PubMed]
- Lee, A.Y.; Raya, A.K.; Kymes, S.M.; Shiels, A.; Brantley, M.A., Jr. Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br. J. Ophthalmol. 2009, 93, 610–613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nischler, C.; Oberkofler, H.; Ortner, C.; Paikl, D.; Riha, W.; Lang, N.; Patsch, W.; Egger, S.F. Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age-related macular degeneration. Acta Ophthalmol. 2011, 89, e344–e349. [Google Scholar] [CrossRef]
- Imai, D.; Mori, K.; Horie-Inoue, K.; Gehlbach, P.L.; Awata, T.; Inoue, S.; Yoneya, S. CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration. J. Ocul. Biol. Dis. Inform. 2010, 3, 53–59. [Google Scholar] [CrossRef] [Green Version]
- Tsuchihashi, T.; Mori, K.; Horie-Inoue, K.; Gehlbach, P.L.; Kabasawa, S.; Takita, H.; Ueyama, K.; Okazaki, Y.; Inoue, S.; Awata, T.; et al. Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration. Ophthalmology 2011, 118, 93–100. [Google Scholar] [CrossRef]
- Kepez, Y.B.; Ozdek, S.; Ergun, M.A.; Ergun, S.; Yaylacioglu, T.F.; Elbeg, S. CFH Y402H and VEGF polymorphisms and anti-VEGF treatment response in exudative age-related macular degeneration. Ophthalmic Res. 2016, 56, 132–138. [Google Scholar] [CrossRef]
- Wang, Z.; Zou, M.; Chen, A.; Liu, Z.; Young, C.A.; Wang, S.B.; Zheng, D.; Jin, G. Genetic associations of anti-vascular endothelial growth factor therapy response in age-related macular degeneration: A systematic review and meta-analysis. Acta Ophthalmol. 2022, 100, e669–e680. [Google Scholar] [CrossRef]
- Park, D.H.; Connor, K.M.; Lambris, J.D. The challenges and promise of complement therapeutics for ocular diseases. Front. Immunol. 2019, 10, 1007. [Google Scholar] [CrossRef]
- Wu, J.; Sun, X. Complement system and age-related macular degeneration: Drugs and challenges. Drug Des. Dev. Ther. 2019, 13, 2413–2425. [Google Scholar] [CrossRef]
- Krebs, I.; Glittenberg, C.; Ansari-Shahrezaei, S.; Hagen, S.; Steiner, I.; Binder, S. Non-responders to treatment with antagonists of vascular endothelial growth factor in age-related macular degeneration. Br. J. Ophthalmol. 2013, 97, 1443–1446. [Google Scholar] [CrossRef] [PubMed]
- Holz, F.G.; Tadayoni, R.; Beatty, S.; Beger, A.; Cereda, M.G.; Cortez, R.; Hoyng, C.B.; Hykin, P.; Staurenghi, G.; Heldner, S.; et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br. J. Ophthalmol. 2015, 99, 220–226. [Google Scholar] [CrossRef] [PubMed]
- Amoaku, W.M.; Chakravarthy, U.; Gale, R.; Gavin, R.; Ghanchi, F.; Gibson, J.; Harding, S.; Johnston, R.L.; Kelly, S.P.; Lotery, A.; et al. Defining response to anti-VEGF therapies in neovascular AMD. Eye (London) 2015, 29, 721–731. [Google Scholar] [CrossRef] [PubMed]
- Ferris, F.L.; Wilkinson, C.P.; Bird, A.; Chakravarthy, U.; Chew, E.; Csaky, K.; Sadda, S.R. Beckman Initiative for Macular Research Classification Committee. Clinical classification of age-related macular degeneration. Ophthalmology 2013, 120, 844–851. [Google Scholar] [CrossRef]
- Klein, M.L.; Francis, P.J.; Rosner, B.; Reynolds, R.; Hamon, S.C.; Schultz, D.W.; Ott, J.; Seddon, J.M. CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 2008, 115, 1019–1025. [Google Scholar] [CrossRef]
- Brantley, M.A., Jr.; Edelstein, S.L.; King, J.M.; Plotzke, M.R.; Apte, R.S.; Kymes, S.M.; Shiels, A. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy. Eye 2009, 23, 626–631. [Google Scholar] [CrossRef] [Green Version]
- Feng, X.; Xiao, J.; Longville, B.; Tan, A.X.; Wu, X.N.; Cooper, M.N.; McAllister, I.L.; Isaacs, T.; Palmer, L.J.; Constable, I.J. Complement factor H Y402H and C-reactive protein polymorphism and photodynamic therapy response in age-related macular degeneration. Ophthalmology 2009, 116, 1908–1912.e1. [Google Scholar] [CrossRef]
- Tan, P.L.; Bowes Rickman, C.; Katsanis, N. AMD and the alternative complement pathway: Genetics and functional implications. Hum. Genom. 2016, 10, 23. [Google Scholar] [CrossRef] [Green Version]
- Sofat, R.; Casas, J.P.; Webster, A.R.; Bird, A.C.; Mann, S.S.; Yates, J.R.W.; Moore, A.T.; Sepp, T.; Cipriani, V.; Bunce, C.; et al. Complement factor H genetic variant and age-related macular degeneration: Effect size, modifiers and relationship to disease subtype. Int. J. Epidemiol. 2012, 41, 250–262. [Google Scholar] [CrossRef]
- Johnson, P.T.; Betts, K.E.; Radeke, M.J.; Hageman, G.S.; Anderson, D.H.; Johnson, L.V. Individual 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 2006, 103, 17456–17461. [Google Scholar] [CrossRef] [Green Version]
- Veloso, C.E.; de Almeida, L.N.; Recchia, F.M.; Pelayes, D.; Nehemy, M.B. VEGF gene polymorphism and response to intravitreal ranibizumab in neovascular age-related macular degeneration. Ophthalmic Res. 2014, 51, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Veloso, C.E.; Almeida, L.N.; Nehemy, M.B. CFH Y402H polymorphism and response to intravitreal ranibizumab in Brazilian patients with neovascular age-related macular degeneration. Rev. Col. Bras. Cir. 2014, 41, 386–392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, H.; Yu, K.D.; Xu, G.Z. Association between variant Y402H in age-related macular degeneration (AMD) susceptibility gene CFH and treatment response of AMD: A meta-analysis. PLoS ONE 2012, 7, e42464. [Google Scholar] [CrossRef] [Green Version]
- Smailhodzic, D.; Muether, P.S.; Chen, J.; Kwestro, A.; Zhang, A.Y.; Omar, A.; Van de Hen, J.P.H.; Keunen, J.E.E.; Kirchhof, B.; Hoyng, C.B.; et al. Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration. Ophthalmology 2012, 119, 2304–2411. [Google Scholar] [CrossRef] [PubMed]
- McKibbin, M.; Ali, M.; Bansal, S.; Baxter, P.D.; West, K.; Williams, G.; Cassidy, F.; Inglehearn, C.F. CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration. Br. J. Ophthalmol. 2012, 96, 208–212. [Google Scholar] [CrossRef]
- Menghini, M.; Kloeckener-Gruissem, B.; Fleischhauer, J.; Kurz-Levin, M.M.; Sutter, F.K.; Berger, W.; Barthelmes, D. Impact of loading phase, initial response and CFH genotype on the long-term outcome of treatment for neovascular age-related macular degeneration. PLoS ONE 2012, 7, e42014. [Google Scholar] [CrossRef] [Green Version]
- Geerlings, M.J.; de Jong, E.K.; den Hollander, A.I. The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment. Mol. Immunol. 2017, 84, 65–76. [Google Scholar] [CrossRef]
- Broadhead, G.K.; Hong, T.; Chang, A.A. Treating the untreatable patient: Current options for the management of treatment-resistant neovascular age-related macular degeneration. Acta Ophthalmol. 2014, 92, 713–723. [Google Scholar] [CrossRef]
- Suzuki, M.; Nagai, N.; Izumi-Nagai, K.; Shinoda, H.; Koto, T.; Uchida, A.; Mochimaru, H.; Yuki, K.; Sasaki, M.; Tsubota, K.; et al. Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration. Br. J. Ophthalmol. 2014, 98, 1186–1191. [Google Scholar] [CrossRef]
- Zuber-Laskawiec, K.; Kubicka-Trzaska, A.; Karska-Basta, I.; Pociej-Marciak, W.; Romanowska-Dixon, B. Non-responsiveness and tachyphylaxis to anti-vascular endothelial growth factor treatment in naive patients with exudative age-related macular degeneration. J. Physiol. Pharmacol. 2019, 70, 779–785. [Google Scholar] [CrossRef]
- Armento, A.; Honisch, S.; Panagiotakopoulou, V.; Sonntag, I.; Jacob, A.; Bolz, S.; Kilger, E.; Deleidi, M.; Clark, S.; Ueffing, M. Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells. Sci. Rep. 2020, 10, 10320. [Google Scholar] [CrossRef] [PubMed]
- Chen, M.; Forrester, J.V.; Xu, H. Synthesis of complement factor h by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp. Eye Res. 2007, 84, 635–645. [Google Scholar] [CrossRef] [PubMed]
- Bhutto, I.A.; Baba, T.; Merges, C.; Juriasinghani, V.; McLeod, D.S.; Lutty, G.A. C-reactive protein and complement factor h in aged human eyes and eyes with age-related macular degeneration. Br. J. Ophthalmol. 2011, 95, 1323–1330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jensen, E.G.; Jakobsen, T.S.; Thiel, S.; Askou, A.L.; Corydon, T.J. Associations between the complement system and choroidal neovascularization in wet age-related macular degeneration. Int. J. Mol. Sci. 2020, 21, 9752. [Google Scholar] [CrossRef]
- Fett, A.L.; Hermann, M.M.; Muether, P.S.; Kirchhof, B.; Fauser, S. Immunohistochemical localization of complement regulatory proteins in the human retina. Histol. Histopathol. 2021, 27, 357–364. [Google Scholar] [CrossRef]
- Cipriani, V.; Lorés-Motta, L.; He, F.; Fathalla, D.; Tilakaratna, V.; McHarg, S.; Bayatti, N.; Acar, I.E.; Hoyng, C.B.; Fauser, S.; et al. Increased circulating levels of Factor H-Related Protein 4 are strongly associated with age-related macular degeneration. Nat. Commun. 2020, 11, 778. [Google Scholar] [CrossRef] [Green Version]
- Keir, L.S.; Firth, R.; Aponik, L.; Feitelberg, D.; Sakimoto, S.; Aguilar, E.; Welsh, G.I.; Richards, A.; Usui, Y.; Satchell, S.C.; et al. VEGF regulates local inhibitory complement proteins in the eye and kidney. J. Clin. Investig. 2017, 127, 199–214. [Google Scholar] [CrossRef] [Green Version]
- Kajander, T.; Lehtinen, M.J.; Hyvärinen, S.; Bhattacharjee, A.; Leung, E.; Isenman, D.E.; Meri, S.; Goldman, A.; Jokiranta, T.S. Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. Proc. Natl. Acad. Sci. USA 2011, 108, 2897–2902. [Google Scholar] [CrossRef] [Green Version]
- Finger, R.P.; Wickremasinghe, S.S.; Baird, P.N.; Guymer, R.H. Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration. Surv. Ophthalmol. 2014, 59, 1–18. [Google Scholar] [CrossRef]
- Hagstrom, S.A.; Ying, G.S.; Pauer, G.J.; Sturgill-Short, G.M.; Huang, J.; Callanan, D.G.; Kim, I.K.; Klein, M.; Maguire, M.G.; Martin, D.F. Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT). Ophthalmology 2013, 120, 593–599. [Google Scholar] [CrossRef] [Green Version]
- Yang, S.; Zhao, J.; Sun, X. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: A comprehensive review. Drug Des. Dev. Ther. 2016, 2, 1857–1867. [Google Scholar] [CrossRef] [Green Version]
- Hara, C.; Wakabayashi, T.; Fukushima, Y.; Sayanagi, K.; Kawasaki, R.; Sato, S.; Sakaguchi, H.; Nishida, K. Tachyphylaxis during treatment of exudative age-related macular degeneration with aflibercept. Graefes Arch. Clin. Exp. Ophthalmol. 2019, 257, 2559–2569. [Google Scholar] [CrossRef] [PubMed]
- Binder, S. Loss of reactivity in intravitreal anti-VEGF therapy: Tachyphylaxis or tolerance? Br. J. Ophthalmol. 2012, 96, 1–2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Arjamaa, O.; Minn, H. Resistance, not tachyphylaxis or tolerance. Br. J. Ophthalmol. 2012, 96, 1153–1154. [Google Scholar] [CrossRef]
- Spencer, K.L.; Hauser, M.A.; Olson, L.M.; Schmidt, S.; Scott, S.; Scott, W.K.; Gallins, P.; Agarwal, A.; Postel, E.A.; Pericak-Vance, M.A.; et al. Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum. Mol. Genet. 2007, 16, 1986–1992. [Google Scholar] [CrossRef]
- Richardson, A.J.; Islam, F.M.A.; Guymer, R.H.; Baird, P.N. Analysis of rare variants in the complement component 2 (C2) and factor B (BF) genes refine association for age-related macular degeneration (AMD). Investig. Ophthalmol. Vis. Sci. 2009, 50, 540–543. [Google Scholar] [CrossRef] [Green Version]
- Havvas, I.; Marioli, D.I.; Deli, A.; Zarkadis, I.K.; Pharmakakis, N. Complement C3, C2,and factor B gene polymorphisms and age-related macular degeneration in a Greek cohort study. Eur. J. Ophthalmol. 2014, 24, 751–760. [Google Scholar] [CrossRef]
- Wu, L.; Tao, Q.; Chen, W.; Wang, Z.; Song, Y.; Sheng, S.; Li, P.; Zhou, J. Association between polymorphisms of complement pathway genes and age-related macular degeneration in a Chinese population. Investig. Ophthalmol. Vis. Sci. 2013, 54, 170–174. [Google Scholar] [CrossRef] [Green Version]
- Pei, X.T.; Li, X.X.; Bao, Y.Z.; Yu, W.Z.; Yan, Z.; Qi, H.J.; Qian, T.; Xiao, H.X. Association of c3 gene polymorphisms with neovascular age-related macular degeneration in a chinese population. Curr. Eye Res. 2009, 34, 615–622. [Google Scholar] [CrossRef]
- Yanagisawa, S.; Kondo, N.; Miki, A.; Matsumiya, W.; Kusuhara, S.; Tsukahara, Y.; Honda, S.; Negi, A. A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population. PLoS ONE 2011, 6, e28847. [Google Scholar] [CrossRef] [Green Version]
- Baatz, H.; Poupel, L.; Coudert, M.; Sennlaub, F.; Combadiere, C. Polymorphisms of complement factor genes and age-related macular degeneration in a German population. Klin. Monbl. Augenheilkd. 2009, 226, 654–658. [Google Scholar] [CrossRef] [PubMed]
- Pociej-Marciak, W.; Karska-Basta, I.; Kuźniewski, M.; Kubicka-Trzaska, A.; Romanowska-Dixon, B. Sudden Visual Deterioration as the First Symptom of Chronic Kidney Failure. Case Rep. Ophtalmol. 2015, 28, 394–400. [Google Scholar] [CrossRef] [PubMed]
Parameter | AMD Group (n = 111) | Control Group (n = 58) | p-Value | |
---|---|---|---|---|
Sex | 0.0624 | |||
Female | 73 (65.8) | 37 (63.8) | ||
Male | 38 (34.2) | 21 (36.2) | ||
Age, y, range (avereage) | 56–90 (71.3) | 54–88 (69.8) | 0.0732 | |
≤60 years | 16 (14.4) | 11 (19.0) | ||
>60 years | 95 (85.6) | 47 (81.0) | ||
Smoking | 0.0796 | |||
Current or former | 34 (30.6) | 15 (25.8) | ||
Never | 77 (69.4) | 43 (74.2) | ||
Living environment | 0.0158 1 | |||
Urban | 77 (69.4) | 36 (62.0) | ||
Rural | 34 (30.6) | 22 (38.0) | ||
Family history of AMD | 0.0021 1 | |||
Positive | 87 (78.4) | 4 (4.0) | ||
Negative | 24 (21.6) | 54 (96.0) |
Parameter | AMD Group (n = 111) | Control Group (n = 58) | Adjusted OR (95% CI) | p-Value for n (%) Compared | |
---|---|---|---|---|---|
Sex | Males | 38 (34.2) | 21 (36.2) | Ref. | 0.0282 1 |
Females | 73 (65.8) | 37 (63.8) | 2.12 (1.09–4.16) | ||
Age | ≤60 years | 16 (14.4) | 11 (19.0) | Ref. | 0.0002 1 |
>60 years | 95 (85.6) | 47 (81.0) | 5.56 (2.23–13.86) | ||
Smoking | Current or former | 34 (30.6) | 15 (25.8) | 0.50 (0.13–1.24) | 0.0831 |
Never | 77 (69.4) | 43 (74.2) | Ref. | ||
Living environment | Urban | 77 (69.4) | 36 (62.0) | 2.65 (1.18–4.95) | 0.0191 1 |
Rural | 34 (30.6) | 22 (38.0) | Ref. | ||
Family history of AMD | Positive | 87 (78.4) | 4 (4.0) | 8.56 (3.64–14.80) | 0.0023 1 |
Negative | 24 (21.6) | 54 (96.0) | Ref. |
Polymorphism | Genotype/Allele | AMD Group (n = 111) | Control Group (n = 58) | Adjusted OR (95% CI) | p-Value for n (%) Compared |
---|---|---|---|---|---|
Y402H rs1061170 (CFH) | TT | 21 (19.0) | 19 (33.0) | Ref. | |
CC | 38 (34.2) | 9 (15.0) | 3.15 (1.24–7.66) | 0.0058 1 | |
CT | 52 (46.8) | 30 (52.0) | 2.52 (1.41–5.68) | 0.5422 | |
T | 94 (52.3) | 68 (58.6) | Ref. | ||
C | 128 (57.7) | 48 (41.4) | 3.98 (1.32–8.47) | 0.0311 1 | |
E318D rs9332739 (C2) | GG | 104 (93.7) | 51 (88.0) | Ref. | |
gc | 7 (6.3) | 7 (12.0) | 0.86 (0.25–1.64) | 0.1154 | |
G | 208 (93.6) | 102 (88.0) | Ref. | ||
g | 7 (3.2) | 7 (6.0) | 0.53 (0.11–1.24) | 0.2330 | |
c | 7 (3.2) | 7 (6.0) | 0.53 (0.11–1.22) | 0.2330 | |
R102G rs2230199 (C3) | GG | 68 (61.3) | 40 (69.0) | Ref. | |
gc | 33 (29.7) | 16 (28.0) | 2.15 (0.43–10.88) | 0.4650 | |
cc | 10 (9.0) | 2 (3.0) | 1.38 (0.62–4.95) | 0.2845 | |
G | 136 (61.2) | 80 (69.0) | Ref. | ||
g | 33 (14.9) | 16 (14.0) | 1.10 (0.85–2.31) | 0.3622 | |
c | 53 (23.9) | 20 (17.0) | 1.68 (1.17–2.24) | 0.5542 |
Variable | Estimated Parameter Value | SE | 95% CI for Estimated Parameter Value | Wald Test | OR | 95% CI for OR | |||
---|---|---|---|---|---|---|---|---|---|
Lower | Upper | χ2 | p-Value | Lower | Upper | ||||
Coefficient β0 | −5.5602 | 1.3962 | −8.3177 | −2.8027 | 15.8596 | 0.0001 | 0.004 | 0.000 | 0.061 |
Sex | 0.7683 | 0.3690 | 0.0396 | 1.4970 | 4.3356 | 0.0373 | 2.156 | 1.040 | 4.468 |
Age | 1.7599 | 0.5076 | 0.7573 | 2.7625 | 12.0193 | 0.0005 | 5.812 | 2.133 | 15.839 |
Living environment | 0.8421 | 0.4001 | 0.0519 | 1.6322 | 4.4303 | 0.0353 | 2.321 | 1.053 | 5.115 |
Family history | 1.6554 | 0.4761 | 0.6545 | 2.3886 | 10.332 | 0.0033 | 8.312 | 3.630 | 14.043 |
CC genotype for rs1061170 | 1.1561 | 0.4480 | 0.2713 | 2.0409 | 6.6587 | 0.0099 | 3.178 | 1.312 | 7.698 |
Parameter | Good Responders | Poor Responders | p-Value | |
---|---|---|---|---|
No. of patients | 83 (74.8) | 28 (25.2) | 0.0001 1 | |
Age, years, range (average) | 56–88 (70.9) | 58–90 (71.6) | 0.8655 | |
First-line anti-VEGF drug number of eyes (%) | Bevacizumab | 31 (37.3) | 12 (42.9) | 0.0633 |
Ranibizumab | 52 (62.7) | 16 (57.1) | 0.0976 | |
Baseline BCVA [LogMAR], range (mean) | 1.5–0.4 (0.5) | 1.4–0.4 (0.5) | 0.0678 | |
Baseline CRT (µm) | 188–605 (342.6) | 201–614 (361.1) | 0.4568 | |
Presence of IRF | 68 (82.0) | 22 (78.6) | 0.4590 | |
Presence of SRF | 39 (47.0) | 11 (39.3) | 0.0853 | |
Presence of sPED | 23 (27.7) | 15 (53.6) | 0.0057 1 | |
Baseline CNV area on FA (mm2), range (average) | 1.2–3.4 (2.24) | 1.1–3.2(2.48) | 0.0830 | |
Genotypes for the CFH gene polymorphism | CC CT TT | 20 (24.1) 40 (48.2) 20 (34.5) | 18 (64.3) 9 (32.1) 1 (3.6) | 0.0002 1 0.0830 0.0001 1 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kubicka-Trząska, A.; Żuber-Łaskawiec, K.; Dziedzina, S.; Sanak, M.; Romanowska-Dixon, B.; Karska-Basta, I. Genetic Variants of Complement Factor H Y402H (rs1061170), C2 R102G (rs2230199), and C3 E318D (rs9332739) and Response to Intravitreal Anti-VEGF Treatment in Patients with Exudative Age-Related Macular Degeneration. Medicina 2022, 58, 658. https://doi.org/10.3390/medicina58050658
Kubicka-Trząska A, Żuber-Łaskawiec K, Dziedzina S, Sanak M, Romanowska-Dixon B, Karska-Basta I. Genetic Variants of Complement Factor H Y402H (rs1061170), C2 R102G (rs2230199), and C3 E318D (rs9332739) and Response to Intravitreal Anti-VEGF Treatment in Patients with Exudative Age-Related Macular Degeneration. Medicina. 2022; 58(5):658. https://doi.org/10.3390/medicina58050658
Chicago/Turabian StyleKubicka-Trząska, Agnieszka, Katarzyna Żuber-Łaskawiec, Sylwia Dziedzina, Marek Sanak, Bożena Romanowska-Dixon, and Izabella Karska-Basta. 2022. "Genetic Variants of Complement Factor H Y402H (rs1061170), C2 R102G (rs2230199), and C3 E318D (rs9332739) and Response to Intravitreal Anti-VEGF Treatment in Patients with Exudative Age-Related Macular Degeneration" Medicina 58, no. 5: 658. https://doi.org/10.3390/medicina58050658