{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T21:46:42Z","timestamp":1784238402120,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T00:00:00Z","timestamp":1605139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Polypoidal choroidal vasculopathy (PCV) is usually regarded as a subtype of choroidal neovascularization (CNV) that is secondary to age-related macular degeneration (AMD) characterized by choroidal vessel branching, ending in polypoidal lesions. Despite their close association, PCV and neovascular AMD have shown differences, especially regarding patients\u2019 treatment response. Currently, antivascular endothelial growth factor (anti-VEGF) drugs, such as ranibizumab, bevacizumab and aflibercept, have demonstrated their efficacy in CNV patients. However, in PCV, anti-VEGF treatments have shown inconclusive results. Many genetic polymorphisms have been associated with a variable response in exudative\/wet AMD patients. Thus, the aim of this study is to explore the genetic variants affecting anti-VEGF drug response in PCV patients. In this regard, we performed a systematic review and meta-analysis. We found four variants (CFH I62V, CFH Y402H, ARMS2 A69S, and HTRA1-62A\/G) that have been significantly related to response. Among them, the ARMS2 A69S variant is assessed in our meta-analysis. In conclusion, in order to implement anti-VEGF pharmacogenetics in clinical routines, further studies should be performed, distinguishing physio-pathogenic circumstances between PCV and exudative AMD and the combined effect on treatment response of different genetic variants.<\/jats:p>","DOI":"10.3390\/genes11111335","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T20:17:52Z","timestamp":1605212272000},"page":"1335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Genetic Variants Affecting Anti-VEGF Drug Response in Polypoidal Choroidal Vasculopathy Patients: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0849-9902","authenticated-orcid":false,"given":"Xando","family":"D\u00edaz-Villamar\u00edn","sequence":"first","affiliation":[{"name":"Pharmacy Department, Hospital Universitario Cl\u00ednico San Cecilio\u2014Instituto de Investigaci\u00f3n Biosanitaria (ibs.Granada), 18016 Granada, Spain"},{"name":"Pfizer-University of Granada-Junta de Andaluc\u00eda Centre for Genomics and Oncological Research (GENYO), 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bl\u00e1nquez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Hospital Universitario de Ceuta, 51003 Ceuta, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-6296","authenticated-orcid":false,"given":"Ana","family":"Pozo-Agundo","sequence":"additional","affiliation":[{"name":"Pfizer-University of Granada-Junta de Andaluc\u00eda Centre for Genomics and Oncological Research (GENYO), 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"P\u00e9rez-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18011 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Ignacio","family":"Mu\u00f1oz-\u00c1vila","sequence":"additional","affiliation":[{"name":"Ophthalmology Department\u2014Hospital Universitario Cl\u00ednico San Cecilio, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3963-6546","authenticated-orcid":false,"given":"Alba","family":"Ant\u00fanez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Pfizer-University of Granada-Junta de Andaluc\u00eda Centre for Genomics and Oncological Research (GENYO), 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Estefan\u00eda","family":"Fern\u00e1ndez-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Hospital Universitario Cl\u00ednico San Cecilio\u2014Instituto de Investigaci\u00f3n Biosanitaria (ibs.Granada), 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Garc\u00eda-Navas","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Hospital Universitario Cl\u00ednico San Cecilio\u2014Instituto de Investigaci\u00f3n Biosanitaria (ibs.Granada), 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2202-0662","authenticated-orcid":false,"given":"Luis Javier","family":"Mart\u00ednez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Pfizer-University of Granada-Junta de Andaluc\u00eda Centre for Genomics and Oncological Research (GENYO), 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina Luc\u00eda","family":"D\u00e1vila-Fajardo","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Hospital Universitario Cl\u00ednico San Cecilio\u2014Instituto de Investigaci\u00f3n Biosanitaria (ibs.Granada), 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.ajo.2003.09.042","article-title":"Choroidal neovascularization","volume":"137","author":"Grossniklaus","year":"2004","journal-title":"Am. J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ajo.2016.07.023","article-title":"Choriocapillaris flow features follow a power law distribution: Implications for characterization and mechanisms of disease progression","volume":"170","author":"Spaide","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1159\/000355488","article-title":"Polypoidal choroidal vasculopathy: Clinical features and genetic predisposition","volume":"231","author":"Honda","year":"2014","journal-title":"Ophthalmologica"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.preteyeres.2009.10.001","article-title":"Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration: Same or different disease?","volume":"29","author":"Laude","year":"2010","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_5","first-page":"1","article-title":"Idiopathic polypoidal choroidal vasculopathy (IPCV)","volume":"32","author":"Yannuzzi","year":"2012","journal-title":"Retina"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.survophthal.2010.03.004","article-title":"Polypoidal choroidal vasculopathy: A review","volume":"55","author":"Imamura","year":"2010","journal-title":"Surv. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4729","DOI":"10.1167\/iovs.08-2134","article-title":"Clinicopathologic findings in polypoidal choroidal vasculopathy","volume":"49","author":"Nakashizuka","year":"2008","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/S0002-9394(02)01404-6","article-title":"Polypoidal choroidal vasculopathy: Natural history","volume":"133","author":"Uyama","year":"2002","journal-title":"Am. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Matsumiya, W., Honda, S., Kusuhara, S., Tsukahara, Y., and Negi, A. (2013). Effectiveness of intravitreal ranibizumab in exudative age-related macular degeneration (AMD): Comparison between typical neovascular AMD and polypoidal choroidal vasculopathy over a 1 year follow-up. BMC Ophthalmol., 13.","DOI":"10.1186\/1471-2415-13-10"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1136\/bjophthalmol-2012-302652","article-title":"Results of 2 years of treatment with as-needed ranibizumab reinjection for polypoidal choroidal vasculopathy","volume":"97","author":"Hikichi","year":"2013","journal-title":"Br. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.ajo.2010.05.026","article-title":"Improvement of angiographic findings of polypoidal choroidal vasculopathy after intravitreal injection of ranibizumab monthly for 3 months","volume":"150","author":"Hikichi","year":"2010","journal-title":"Am. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1097\/IAE.0b013e31824f91e8","article-title":"EVEREST study: Efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy","volume":"32","author":"Koh","year":"2012","journal-title":"Retina"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1136\/bjo.2008.150029","article-title":"Continuous anti-VEGF treatment with ranibizumab for polypoidal choroidal vasculopathy: 6-month results","volume":"94","author":"Kokame","year":"2010","journal-title":"Br. J. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1007\/s10384-010-0813-1","article-title":"Treatment of polypoidal choroidal vasculopathy by intravitreal injection of bevacizumab","volume":"54","author":"Tsujikawa","year":"2010","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.ophtha.2007.10.018","article-title":"Guidelines for PDT in Japan","volume":"115","author":"Tano","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ophtha.2007.02.031","article-title":"One-year outcomes of photodynamic therapy in age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese patients","volume":"115","author":"Gomi","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.ajo.2010.05.035","article-title":"Polypoidal choroidal vasculopathy masquerading as neovascular age-related macular degeneration refractory to ranibizumab","volume":"150","author":"Stangos","year":"2010","journal-title":"Am. J. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1097\/IAE.0b013e3181f274ec","article-title":"Photodynamic therapy, ranibizumab, and ranibizumab with photodynamic therapy for the treatment of polypoidal choroidal vasculopathy","volume":"31","author":"Rouvas","year":"2011","journal-title":"Retina"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ajo.2013.04.029","article-title":"Anti-vascular endothelial growth factor monotherapy in the treatment of submacular hemorrhage secondary to polypoidal choroidal vasculopathy","volume":"156","author":"Cho","year":"2013","journal-title":"Am. J. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1159\/000354072","article-title":"Polypoidal choroidal vasculopathy exudation and hemorrhage: Results of monthly ranibizumab therapy at one year","volume":"231","author":"Kokame","year":"2014","journal-title":"Ophthalmologica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/clpt.2012.96","article-title":"Pharmacogenomics knowledge for personalized medicine","volume":"92","author":"McDonagh","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.ophtha.2013.11.035","article-title":"The IL-8, VEGF, and CFH polymorphisms and bevacizumab in age-related macular degeneration","volume":"121","author":"Kivioja","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"623","DOI":"10.2217\/pgs.13.43","article-title":"VEGF-Apolymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration","volume":"14","author":"Lazzeri","year":"2013","journal-title":"Pharmacogenomics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ophtha.2012.10.006","article-title":"Variants in the VEGFA gene and treatment outcome after anti-VEGF treatment for neovascular age-related macular degeneration","volume":"120","author":"Abedi","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.1016\/j.ophtha.2012.05.040","article-title":"Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration","volume":"119","author":"Smailhodzic","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1159\/000439172","article-title":"Pharmacogenetic effect of complement factor H gene polymorphism in response to the initial intravitreal injection of bevacizumab for wet age-related macular degeneration","volume":"54","author":"Medina","year":"2015","journal-title":"Ophthalmic Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/eye.2008.28","article-title":"Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to photodynamic therapy","volume":"23","author":"Brantley","year":"2008","journal-title":"Eye"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/FPC.0000000000000180","article-title":"A genetic variant in NRP1 is associated with worse response to ranibizumab treatment in neovascular age-related macular degeneration","volume":"26","author":"Muether","year":"2016","journal-title":"Pharm. Genom."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"779","DOI":"10.2217\/pgs.12.53","article-title":"Association of genetic polymorphisms with response to bevacizumab for neovascular age-related macular degeneration in the Chinese population","volume":"13","author":"Tian","year":"2012","journal-title":"Pharmacogenomics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14517","DOI":"10.1038\/srep14517","article-title":"Pharmacogenetics of complement factor H Y402H polymorphism and treatment of neovascular AMD with anti-VEGF agents: A meta-analysis","volume":"5","author":"Chen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhou, Y.-L., Chen, C., Wang, Y.-X., Tong, Y., Fang, X.-L., Li, L., and Wang, Z.-Y. (2017). Association between polymorphism rs11200638 in the HTRA1 gene and the response to anti-VEGF treatment of exudative AMD: A meta-analysis. BMC Ophthalmol., 17.","DOI":"10.1186\/s12886-017-0487-2"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1136\/bjophthalmol-2014-305488","article-title":"Association between variants A69S in ARMS2 gene and response to treatment of exudative AMD: A meta-analysis","volume":"99","author":"Hu","year":"2015","journal-title":"Br. J. Ophthalmol."},{"key":"ref_33","unstructured":"Wells, G., Shea, B., O\u2019connell, D., Peterson, J., Welch, V., Losos, M., and Tugwell, P. (2011). The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses, Ottawa Hospital Research Institute."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Park, U.C., Shin, J.Y., Chung, H., and Yu, H.G. (2017). Association of ARMS2 genotype with response to anti-vascular endothelial growth factor treatment in polypoidal choroidal vasculopathy. BMC Ophthalmol., 17.","DOI":"10.1186\/s12886-017-0631-z"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1097\/IAE.0b013e318225290f","article-title":"LOC387715\/HTRA1 variants and the response to combined photodynamic therapy with intravitreal bevacizumab for polypoidal choroidal vasculopathy","volume":"32","author":"Park","year":"2012","journal-title":"Retina"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1007\/s00417-014-2838-5","article-title":"Effects of aflibercept for ranibizumab-resistant neovascular age-related macular degeneration and polypoidal choroidal vasculopathy","volume":"253","author":"Kawashima","year":"2015","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00417-014-2688-1","article-title":"Two-year visual outcome of ranibizumab in typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy","volume":"253","author":"Hata","year":"2015","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00417-014-2675-6","article-title":"Two-year visual outcome of polypoidal choroidal vasculopathy treated with photodynamic therapy combined with intravitreal injections of ranibizumab","volume":"253","author":"Hata","year":"2015","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s10384-019-00683-6","article-title":"Association of an age-related maculopathy susceptibility 2 gene variant with the 12-month outcomes of intravitreal aflibercept combined with photodynamic therapy for polypoidal choroidal vasculopathy","volume":"63","author":"Nakai","year":"2019","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Yamashiro, K., Hosoda, Y., Miyake, M., Ooto, S., and Tsujikawa, A. (2020). Characteristics of pachychoroid diseases and age-related macular degeneration: Multimodal imaging and genetic backgrounds. J. Clin. Med., 9.","DOI":"10.3390\/jcm9072034"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1016\/j.ophtha.2016.06.060","article-title":"Risk alleles associated with neovascularization in a pachychoroid phenotype","volume":"123","author":"Dansingani","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7188","DOI":"10.1038\/s41598-020-64301-z","article-title":"Genetic factors associated with response to as-needed aflibercept therapy for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy","volume":"10","author":"Yoneyama","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_44","first-page":"221","article-title":"Altered oxidative stress in healthy old subjects","volume":"9","author":"Rondanelli","year":"1997","journal-title":"Aging"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1006\/exer.2001.1094","article-title":"Complement activation and inflammatory processes in Drusen formation and age related macular degeneration","volume":"73","author":"Johnson","year":"2001","journal-title":"Exp. Eye Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1001\/jama.296.3.301","article-title":"Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration","volume":"296","author":"Despriet","year":"2006","journal-title":"JAMA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.preteyeres.2016.04.003","article-title":"Risk factors and biomarkers of age-related macular degeneration","volume":"54","author":"Lambert","year":"2016","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12974-016-0776-3","article-title":"Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator","volume":"14","author":"Micklisch","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1007\/s00417-017-3748-0","article-title":"ARMS2 A69S polymorphism is associated with the number of ranibizumab injections needed for exudative age-related macular degeneration in a pro re nata regimen during 4 years of follow-up","volume":"255","year":"2017","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/11\/1335\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:32:29Z","timestamp":1760178749000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/11\/1335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,12]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["genes11111335"],"URL":"https:\/\/doi.org\/10.3390\/genes11111335","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,12]]}}}