GENETIC CRITERIA FOR ANTI-ANGIOGENIC THERAPY FOR TREATMENT OF DIABETIC MACULAR EDEMA

Apart from already established clinical factors, the polymorphic loci of the VEGF gene and its VEGFR2 receptor can have a significant effect on the response to anti-VEGF therapy of diabetic macular edema. The aim was to study the association of single nucleotide polymorphic loci of VEGF and VEGFR2 genes, as well as functional and anatomical parameters with response to ranibizumab therapy in patients with diabetic macular edema. Material and methods. The study includes 145 patients (145 eyes) with diabetic macular edema. All the patients are divided into 2 groups: a positive response (A) and no response to angiogenic therapy (B). The positive response (group A) was the presence of a reduction of at least 10 % of the foveolar thickness (FT) from the baseline according to the OST data. In addition, the response category was assessed: a good response (A1): a reduction in FT by more than 25 %, and an increase in MCHO by more than 5 letters of ETDRS and a poor response (group A2): a reduction in FT of 10-25 % and an increase in MCRI by less than 5 letters ETDRS. Genomic DNA was selected from leukocytes in venous blood, genotyping was performed by real-time PCR using probes of hydrolysing samples. Results. 45 (33.6 %) patients demonstrated a good response (group A1) to therapy and 89 (66.4 %) had a «bad» response (group A2). In group A1, the decrease in FT occurred on average by 25.61 %, the increase in MHC was 0.21 ± 0.07, while in group A2, the visual acuity increased by 0.05, with the thickness of the retina reduction by 74.1 μm (19, 5 %). Rs3025039 of the VEGFA gene is associated with the change in PTC ( p = 0.02). The decrease in the volume of the macula is associated with the allele C rs2010963 of the VEGFA gene ( p = 0.03). For the carriers of the T allele, the locus rs3025039 of the VEGFA gene, on the contrary, shows a lower value of the decrease in the volume of the macula ( p = 0.03). The patients with the T / T genotype of the polymorphic locus rs3025039 of the VEGFA gene statistically respond to anti-VEGF therapy significantly worse.

diffuse macular edema, optical coherence tomography, foveolar thickness of retina, ranibizumab

1. Алгоритмы специализированной медицинской помощи больным сахарным диабетом / ред. И.И. Дедов, М.В. Шестакова // Сах. диабет. 2015. 18. (1S). 1-112.

2. Al-Habboubi H.H., Sater M.S., Almawi A.W., Al-Khateeb G.M., Almawi W.Y. Contribution of VEGF polymorphisms to variation in VEGF serum levels in a healthy population // Eur. Cytokine Netw. 2011. 22. 154-158.

3. Bieche I., Vacher S., Vallerand D., Richon S., Hatem R., de Plater L., Dahmani A., Nemati F., Angevin E., Marangoni E., Roman-Roman S., Decaudin D., Dangles-Marie V. Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings // BMC Cancer. 2014. 14. 39-45.

4. Bressler S.B., Ayala A.R., Bressler N.M., Melia M., Qin H., Ferris F.L., Flaxel C.J., Friedman S.M., Glassman A.R., Jampol L.M., Rauser M.E. Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment //JAMA Ophthalmol. 2016. 134. 278-285.

5. Bressler S.B., Qin H., Beck R.W., Chalam K.V., Kim J.E., Melia M., Wells J.A. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab // Arch. Ophthalmol. 2012. 130. 1153-1161.

6. Chen C.-F., Liou S.-W., Wu H.-H., Lin C.-H., Huang L.-S., Woung L.-C., Tsai C.Y. Regulatory SNPs alter the gene expression of diabetic retinopathy associated secretary factors // Int. J. Med. Sci. 2016. 13. 717-723.

7. Committee W., Aiello L.P., Beck R.W., Bressler N.M., Browning D.J., Chalam K.V., Davis M., Ferris F.L., 3rd, Glassman A.R., Maturi R.K., Stockdale C.R., Topping T.M. Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema // Ophthalmology. 2011. 118. 5-14.

8. El-Shazly S.F., El-Bradey M.H., Tameesh M.K. Vascular endothelial growth factor gene polymorphism prevalence in patients with diabetic macular edema and its correlation with anti-VEGF treatment outcomes //Clin. Experiment. Ophthalmol. 2013. 3. 23-29.

9. Elman M.J., Qin H., Aiello L.P., Beck R.W., Bressler N.M., Ferris F.L., Glassman A.R., Maturi R.K., Melia M. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results // Ophthalmology. 2012. 119. 2312-2318.

10. Funatsu H., Yamashita H., Sakata K., Noma H., Mimura T., Suzuki M., Eguchi S., Hori S. Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule 1 are related to diabetic macular edema // Ophthalmology. 2005. 112. 806-816.

11. Klein R., Klein B.E.K., Moss S.E., Davis M.D., DeMets D.L. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema // Ophthalmology. 1984. 91. 1464-1474.

12. Lu M., Perez V.L., Ma N., Miyamoto K., Peng H.B., Liao J.K., Adamis A.P. VEGF increases retinal vascular ICAM-1 expression in vivo // Invest. Ophthalmol. Vis. Sci. 1999. 40. 1808-1812.

13. Shadrina A.S., Smetanina M.A., Sokolova E.A., Shamovskaya D.V., Sevost’ianova K.S., Shevela A.I., Soldatsky E.Y., Seliverstov E.I., Demekhova M.Y., Shonov O.A., Ilyukhin E.A., Voronina E.N., Pikalov I.V., Zolotukhin I.A., Kirienko A.I., Filipenko M.L. Allele rs2010963 C of the VEGFA gene is associated with the decreased risk of primary varicose veins in ethnic Russians // Phlebology. 2016. 31. 34-38.

14. Sokolova E.A., Malkova N.A., Korobko D.S., Rozhdestvenskii A.S., Kakulya A.V., Khanokh E.V., Delov R.A., Platonov F.A., Popova T.Y., Aref’ eva E.G., Zagorskaya N.N., Alifirova V.M., Titova M.A., Smagina I.V., El’chaninova S.A., Popovtseva A.V., Puzyrev V.P., Kulakova O.G., Tsareva E.Y., Favorova O.O., Shchur S.G., Lashch N.Y., Popova N.F., Popova E.V., Gusev E.I., Boyko A.N., Aulchenko Y.S., Filipenko M.L. Association of SNPs of CD40 gene with multiple sclerosis in Russians // PLoS One. 2013. 8. e61032.

15. Sophie R., Lu N., Campochiaro P.A. Predictors of functional and anatomic outcomes in patients with diabetic macular edema treated with ranibizumab // Ophthalmology. 2015. 122. 1395-1401.

16. Wang Y., Zheng Y., Zhang W., Yu H., Lou K, Zhang Y., Qin Q., Zhao B., Yang Y., Hui R. Polymorphisms of KDR gene are associated with coronary heart disease // J. Am. Coll. Cardiol. 2007. 50. 760-767.

17. Stewart M.W. Anti-VEGF therapy for diabetic macular edema // Curr. Diab. Rep. 2014. 14. 23-29.

18. Vailati F.B., Crispim D., Sortica D.A., Souza B.M., Brondani L.A., Canani L.H. The C allele of -634G/C polymorphism in the VEGFA gene is associated with increased VEGFA gene expression in human retinal tissue // Investig. Opthalmol. Vis. Sci. 2012. 53. 64-71.