DNA methyltransferase expression (DNMT1, DNMT3a and DNMT3b) as a potential biomarker for anti-VEGF diabetic macular edema response

Abstract

Purpose DNA methylation is involved in Diabetic Retinopathy progression showing a metabolic memory mechanism. However, the association of DNA methyltransferase with diabetic macular edema is still unknown. We aimed to describe the differences in DNA methyltransferase gene expression in patients with different diabetic macular edema responses. Methods A total of 27 diabetic patients, aged 59–90 years, were prospectively enrolled in this cross-sectional study. The participants were classified into control group (CG, n = 11), diabetic macular edema responders (rDME, n = 9) and non-responder diabetic macular edema (nrDME, n = 7) after anti-vascular endothelial growth factor (anti-VEGF) treatment. Only cases with a complete ophthalmological examination, digital 133° color fundus, and SD-OCT assessments were used. After RNA extraction and first-strand cDNA synthesis, quantitative real-time PCR was performed with specific primers on the CFX Connect™ Real-Time PCR Detection System to assess differential transcriptional expression patterns. Results The DNMT1 gene showed a positive correlation (r = 0.617; p = 0.043) with Best Corrected Visual Acuity (BCVA) in CG, a positive correlation (r = 0.917; p = 0.010) with HbA1c in nrDME and a negative correlation (r = −0.659; p = 0.049) with GCL-IPL thickness in rDME. DNMT3A gene showed a positive correlation (r = −0.890; p = 0.001) with Sub-foveal Choroidal thickness in rDME whereas DNMT3b gene showed a negative correlation (r = −0.815; p = 0.007) with HbA1c and RNFL (r = −0.664; p = 0.026) in CG. Conclusions Patients with similar metabolic profile risk factors showed associated DNA methyltransferase transcriptional expression patterns differences fitting with the anti-VEGF diabetic macular edema response. Further studies are needed to clarify if these results (1) reflect disease evolution, (2) translate the therapeutic impact, (3) or can help to predict the therapeutic resistance profile.

WNT-inhibitory factor 1-mediated glycolysis protects photoreceptor cells in diabetic retinopathy

“…Extensive population studies have consistently reported a significant decline in visual acuity and ERG responses in individuals with PDR, and the presence of neurodegeneration in all phenotypes of DR [ 55 , 56 ]. The shortened and disorganized photoreceptor outer segments contribute to a reduction in a-wave amplitude [ 57 ].…”

The role of TET2-mediated ROBO4 hypomethylation in the development of diabetic retinopathy

“…The advent of anti-VEGF therapy demonstrated remarkable clinical benefits; however, the majority of patients failed to achieve clinically significant visual improvement, and there are limitations such as some cases lacking response to anti-VEGF therapy and short half-life of drugs requiring repeated injection [ 4 ], so it is urgent to develop new therapeutic methods. According to a recent clinical study on patients with diabetic macular edema, patients who were insensitive to the anti-VEGF response had significantly higher levels of DNMT1 expression than patients who were sensitive to it [ 51 ]. This finding raises the possibility that regulating DNA methylation may be crucial to the complementary treatment of DR.…”