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International Ophthalmology

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01-12-2018 | Original Paper

VEGF-A gene polymorphisms and responses to intravitreal ranibizumab treatment in patients with diabetic macular edema

Authors: Mehmet Tetikoğlu, Zafer Yüksel, Serdar Aktas, Haci Murat Sağdik, Fatih Özcura

Published in: International Ophthalmology | Issue 6/2018

Abstract

Purpose

To investigate the association between VEGF gene polymorphisms and the responses to treatment with intravitreal ranibizumab (IVR) in patients with diabetic macular edema (DME).

Methods

This prospective study, conducted at the Kutahya Dumlupinar University Faculty of Medicine, included 95 patients with DME that were treated with IVR and 32 patients without DME despite proliferative diabetic retinopathy (PDR). The participants were divided into three groups: DME with non-proliferative diabetic retinopathy, DME with PDR, and PDR without DME; patients with DME who were treated with IVR were further divided into two groups based on their response to the treatment. Each patient was genotyped for five single nucleotide variations (SNVs) in VEGF-A: rs2010963, rs2146323, rs10434, rs833069, and rs6921438.

Result

There was a statistically significant difference in allelic distribution of VEGF-A rs833069 polymorphism in relation to the severity of diabetic retinopathy (DRP) (p = 0.031). The allelic distribution of VEGF-A rs2146323 polymorphism tended to be associated with the severity of DRP (p = 0.069). There were no statistically significant differences in the allelic distribution of the studied five SNVs in DME patients regarding the patients’ responses to IVR therapy.

Conclusions

There is no association between the studied VEGF-A SNVs and the responses to IVR therapy in DME. However, the VEGF-A rs833069 gene polymorphism has a clear association with the severity of diabetic retinopathy.

Congdon N, O’Colmain B, Klaver CC, Klein R, Muñoz B, Friedman DS et al (2004) Cause and prevalence of visual impairment among adults in the United State. Arch Ophthalmol 122:477–485CrossRef

Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW et al (2004) The evolving diabetes burden in the United State. Ann Intern Med 140:945–950CrossRef

Klein R, Klein BE, Moss SE, Davis MD, DeMets DL (1984) The Wisconsin epidemiologic study of diabetic retinopathy: IV. Diabetic macular edema. Ophthalmology 91(12):1464–1474CrossRef

Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE (2009) The wisconsin epidemiolojik study of diabetic retinopathy XXIII: the twenty five year incidence of macular in person with type 1 diabets. Ophthalmology 116(3):497–503CrossRef

Bahagat N, Grigorian RA, Tutela A, Zarbin MA (2009) Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol 54:1–31CrossRef

Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487CrossRef

Ferrara N, Damico L, Shams N, Lowman H, Kim R (2006) Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26:859–870CrossRef

Yu L, Liang XH, Ferrara N (2011) Comparing protein VEGF inhibitors: in vitro biological studies. Biochem Biophys Res Commun 408:276–281CrossRef

Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS (2012) Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 130:1145–1152CrossRef

10.

Ip M, Domalpally A, Sun J, Ehrlich JS (2015) Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for retinopathy worsening. Ophthalmology 122:367–374CrossRef

11.

The Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR et al (2010) Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 117:1064–1077CrossRef

12.

The Diabetic Retinopathy Clinical Research Network, Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL, Friedman S (2011) Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 118:609–614CrossRef

13.

Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, On behalf of the RIDE and RISE Research Group et al (2013) Long-term outcome of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trial: RIDE and RISE. Ophthalmology 120:2013–2022CrossRef

14.

Yang X, Deng Y, Gu H, Ren X, Li N, Lim A et al (2014) Candidate gene association study for diabetic retinopathy in Chinese patients with type 2 diabets. Mol Vis 20:200–214PubMedPubMedCentral

15.

Gong JY, Sun YH (2013) Association of VEGF gene polymorphisms with diabetic retinopathy: a meta-analysis. PLos One 8:e84069CrossRef

16.

Churchill AJ, Carter JG, Ramsden C, Turner SJ, Yeung A, Brenchley PE et al (2008) VEGF polymorphisms are associated with severity of diabetic retinopathy. Investig Ophthalmol Vis Sci 49:3611–3616CrossRef

17.

Wirostko B, Wong TY (2008) Simo R Vascular endothelial growth factor and diabetic complications. Prog Retin Eye Res 27:608–662CrossRef

18.

Malecaze F, Clamens S, Simorre-Pinatel V, Mathis A, Chollet P, Favard C et al (1994) Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch Ophthalmol 112:1476–1482CrossRef

19.

Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L et al (1995) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci 92:10457–10461CrossRef

20.

Lally DR, Shah CP, Heier JS (2016) Vascular endothelial growth factor and diabetic macular edema. Surv Ophthalmol 61(6):759–768CrossRef

21.

Wood EH, Karth PA, Moshfeghi DM, Leng T (2015) Short term outcomes of aflibercept therapy for diabetic macular edema in patients with incomplete response to ranibizumab and/or bevacizumab. Ophthalmic Surg Lasers Imaging Retin 46(9):950–954CrossRef

22.

Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V, Hutchinson IV (1999) Novel polymorphisms in the promoter and 5′ UTR regions of the human vascular endothelial growth factor gene. Hum Immunol 60:1245–1249CrossRef

23.

Awata T, Inoue K, Kurihara S, Hutchinson JA, Pravica V, Hutchinson IV (2002) A common polymorphism in the 5′-untranslated region of the vegf gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51:1635–1639CrossRef

24.

Hagstrom SA, Ting GS, Pauer GJ, Sturgill-Short GM, Huang J, Maguire MG, CATT Research Group et al (2014) VEGFA and VEGFR2 gene polymorphisms and response: comparison of age-related macular degeneretion treatments trials (CATT). JAMA Ophthalmol 132:521–527CrossRef

25.

Galan A, Ferlin A, Caretti L, Buson G, Sato G, Frigo AC et al (2010) Association of age-related macular degeneration with polymorphisms in vascular endothelial growth factor and its receptor. Ophthalmology 117(9):1769–1774CrossRef

26.

Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agarwal A, Postel EA et al (2006) Functional candidate genes in age-related macular degeneration: significant association with VEGF, VDRLR, and LRP6. Investig Ophthalmol Vis Sci 47(1):329–335CrossRef

27.

Chang W, Noh DH, Sagong M, Kim IT (2013) Pharmacogenetic association with early response to intravitreal ranibizumab for age-relaed macular degeneration in a Korean population. Mol Vis 19:702–709PubMedPubMedCentral

28.

Al-Kateb H, Mirea L, Xie X, Sun L, Liu M, Chen H et al (2007) Multiple variants in vascular endothelial growth factor (VEGFA) are risk factors for time to severe retinopathy in type 1 diabetes. Diabetes 56(8):2161–2168CrossRef

29.

Zeng Y, Dai F, Yang K, Tang Y, Xu M, Zhou Y (2015) Association between a vascular endothelial growth factor gene polymorphism (rs2146323) and diabetic retinopathy: a meta-analysis. BMC Ophthalmol 15:163CrossRef

30.

Nakanishi K, Watanabe C (2009) Single nucleotide polymorphisms of vascular endothelial growth factor gene intron 2 are markers for early progression of diabetic retinopathy in Japanese with type 1 diabetes. Clin Chim Acta 402:171–175CrossRef

31.

Abhary S, Burdon KP, Gupta A, Lake S, Selva D, Petrovsky N et al (2009) Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy. Investig Ophthalmol Vis Sci 50:5552–5558CrossRef

32.

Vailati FB, Crispim D, Sortica DA, Souza BM, Brondani LA, Canani LH (2012) The C allele of -634G/C polymorphism in the VEGFA gene is associated with increased VEGFA gene expression in human retinal tissue. Investig Ophthalmol Vis 53:6411–6415CrossRef

33.

Awata T, Kurihara S, Takata N, Neda T, Iizuka H, Ohkubo T et al (2005) Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes. Biochem Biophys Res Commun 333:679–685CrossRef

34.

El-Shazly SF, El-Bradey MH, Tameesh MK (2014) Vascular endothelial growth factor gene polymorphism prevalence in patients with diabetic macular edema and its correlation with anti-vascular endothelial growth factor treatment outcomes. Clin Exp Ophthalmol 42:369–378CrossRef

35.

Debette S, Visvikis-Siest S, Chen MH, Ndiaye NC, Song C, Destefano A et al (2011) Identification of cis-and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels. Circ Res 109:554–563CrossRef

Title: VEGF-A gene polymorphisms and responses to intravitreal ranibizumab treatment in patients with diabetic macular edema
Authors: Mehmet Tetikoğlu
Zafer Yüksel
Serdar Aktas
Haci Murat Sağdik
Fatih Özcura
Publication date: 01-12-2018
Publisher: Springer Netherlands
Published in: International Ophthalmology / Issue 6/2018
Print ISSN: 0165-5701
Electronic ISSN: 1573-2630
DOI: https://doi.org/10.1007/s10792-017-0738-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

VEGF-A gene polymorphisms and responses to intravitreal ranibizumab treatment in patients with diabetic macular edema

Abstract

Purpose

Methods

Result

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Result

Conclusions

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