Age-related macular degeneration mainly affects the elderly and is one of the most common causes of rapidly progressive vision loss. Over more than 150 years of research, the scientific community has gone from understanding the macroscopic picture of the lesion, presumable identification of drusen as the main morphological manifestation of nosology, to detailed classifications and determine the role of genetic determinants in the etiopathogenesis of the disease — high specificity, the possibility of preventive analysis, and much unclear in the field of genetic diagnosis of eye diseases determine the accurate attention of specialized research groups to the early diagnosis using genetic analysis. The review article was aimed to systematize the information about possible links in the pathogenesis of age-related macular degeneration and identify potential polymorphisms that can initiate and modulate the activity of these links. During the study, we could find out five main mechanisms of damage to the vascular membrane of the eye itself, which are affected by single nucleotide polymorphisms. The highest affinity was shown by genetic variants of separate sites of CFH (rs1061170), HTRA1 (rs11200638), TNF (rs1800629), VEGFA (rs2010963). Literature data obtained from foreign and national sources indexed by Scopus, Web of Science databases, in particular for the last 5 years, pay special attention to these areas as potential predictors or modifiers of pathological processes involved in the process of macular degeneration. Despite the large number of studies examining the predisposition, pathogenesis, diagnosis, and treatment of age-related macular degeneration to stop the spread of vision loss, only a few issues are understood thoroughly. Considering the successful cases of application of biological and gene therapy for the management of such patients, we see new horizons in the detailed study of molecular interactions that underlie the pathology. The review confirms the active role of polymorphisms in one of the most relevant pathological processes of the human eye.
Introduction. Age-related macular degeneration (AMD) of the retina is still considered the leading cause of vision loss in the elderly. The multifactoriality of the disease impairs the clinical effectiveness of modern AMD treatment methods. however, the study of single-nucleotide polymorphisms, in particular, of the HtrA serine peptidase 1 (HTRA1), vascular endothelial growth factor A (VEGF A) and tumor necrosis factor (TNF) genesis a promising link on the way to improve and develope more effective treatment strategies of the disease. The Aim of the Study. To investigate role of HTRA 1, VEGF A and TNF gene polymorphisms in the treatment of wet age-related macular degeneration. Materials and Methods. 162 people with diagnosed wet AMD took part in the investigation. They received anti-VEGF A therapy in the form of injections of aflibercept monthly for half a year. Structural changes of the eyes were studied using optical coherence tomography (OCT); polymerase chain reaction (PCR) studies were performed using a Bio-Rad CFX 96 apparatus (BioRad, USA) using a reagent package (Lytech, Russia). Statistical analysis of the obtained results was performed using a set of software packages Statistica 10 (StatSoft, Inc., USA) and SPSS 23.0. Results. It was revealed best prognostic significance in patients with the TC rs2010963 genotype of the VEGFA gene was registered during the analysis of OCT 2 (RR=2.7; 95% CI 1.556 – 4.8), OCT 4 (RR=2.9 ; 95% CI 1.7 – 5.03) and OCT 8 (RR=2.6; 95% CI 1.6 – 4.12) sections, while in patients with the CC genotype these indicators in the OCT 2 section were: RR= 6.1; 95% CI 3.66 – 10.27; in OCT zone 4 RR=4.9; 95% CI 2.9 – 8.29, and in the OCT section 8: RR=4.23; 95% CI 2.7 – 6.556, which indicates a more pronounced influence of the CC genotype. When analyzing rs1800629 of the TNF gene, the best prognostic significance of the GA genotype was established in the OCT 4 (RR=1.77; 95% CI 1.218 – 2.56) and OCT 8 (RR=1.9; 95% CI 1.17 – 3.175) areas (p-value less than 0.05), with the AA genotype in OCT 4 (RR=3.77; 95% CI 2.17 – 6.58), OCT 8 (RR=3.1; 95% CI 1 .7 – 5.59) zones and when evaluating changes in visual acuity of patients with wet AMD (RR=4.2; 95% CI 2 – 8.98). No statistically significant results were found in the evaluation of the HTRA1 gene rs11200638 (p-value more than 0.05). Conclusions. The data obtained in our study indicate a direct influence of the vascular endothelial growth factor A (rs2010963) and tumor necrosis factor (rs1800629) polymorphisms on the emergence of resistance to aflibercept. However, the study of this influence in the presence of the HtrA serine peptidase 1 gene rs11200638 requires further research.
Annotation. Age-related macular degeneration is one of the main causes of vision loss in the elderly. By 2040, the population with age-related macular degeneration (AMD) is expected to reach about 288 million. It was hypothesized that anti-VEGF therapy would significantly improve the vision and quality of life of patients with “wet” AMD. However, approximately one-third of patients do not benefit from this therapy, including due to macular fibrosis or retinal atrophy. It is believed that the role of genetic predisposition may also influence treatment resistance. Therefore, the aim of the study was to identify the response to treatment with aflibercept in patients with “wet” AMD with polymorphism variants rs2010963 of the VEGFA gene. The research group included 162 people who had a confirmed “wet” form of AMD, in contrast to which 105 people were included in the comparison group. The “wet” form of AMD was detected with the help of optical coherence tomography using the ILM-RPE parameter, while the patients received monthly intravitreal injections of the AVGF drug aflibercept (50 μl of solution – the recommended dose). Real-time polymerase chain reaction was used to determine the rs2010963 polymorphism of the VEGFA gene. Statistical processing of the obtained results was carried out using Statistica 10.0 and SPSS 23.0 programs. It was established that the presence of the mutant C allele increases the risk of resistance to anti-VEGF therapy both after the first injection and after the full course of treatment (p<0.05). A strong influence of the polymorphism after the therapy was observed in the areas of OCT 2, which corresponds to the inner upper part of the retina (OR=5.89; 95% CI 3.31 – 10.49) and OCT 3, which corresponds to the central area of the retina (OR=4, 76; 95% CI 2.79 – 8.13). At the same time, there is an influence of mutant genotypes on treatment: yes, carrying both the heterozygous variant of ONP and the homozygous variant for the minor allele significantly contributed to the emergence of resistance to treatment (p<0.05). A pronounced degree of association of rs2010963 of the VEGFA gene with the emergence of resistance to the action of anti-VEGF drugs was revealed. Thus, the heterogeneity of RR and 95% CI indicators in different areas of the retina likely indicates a “zone-dependent” effect of rs2010963 of the VEGFA gene on the retina, which may be related to the peculiarities of its functioning and pathogenetic effect on the organ of vision.
Annotation. Age-related macular degeneration (AMD) includes pathological changes in the deep layers of the retina, macula, and surrounding blood vessels, leading to loss of central vision. The wet form of nosology is the leading cause of irreversible blindness in developed countries among people over 60, where more than 30 million people suffer from the disease. The number of patients in the United States is expected to increase from 9.1 million in 2010 to 17.8 million in 2050. New therapeutic strategies and the development of new practical methods for identifying patients at high risk of treatment resistance are needed to reduce the prevalence of the disease. That is why the aim of the study was to shed light on the role of the rs1800629 polymorphism of the TNF gene as one of the prognostic factors in the effectiveness of treatment of the wet form of AMD. The study group consisted of 162 people diagnosed with a wet form of pathology, while the comparison group consisted of 105 people without a history of ophthalmic pathology. Optical coherence tomography of certain areas of the eye, including the retina, was used to confirm or rule out the diagnosis. To detect the polymorphism status of the TNF gene, the real-time polymerase chain reaction method was used on the BioRad CFX 96 thermocycler-amplifier, using “Litekh” (RF) reagent kits. Statistical processing of the results was performed by determining the Hardy-Weinberg equilibrium, Student’s and Wilcoxon’s criteria, logistic regression using OR values and 95% CI, and by subtracting RR and χ². The study found that the frequency of genotype distribution with mutant allele A was predominant among patients in the study group, and the G allele was determined predominantly in the control group and was associated with better results of anti-VEGF therapy. The results of OCT confirmed this information, because among carriers of genotypes GG and GA (p<0.05) visual acuity improved even after the first injection of the drug in most areas, while among carriers of homozygous genotype AA was not sufficient probability of biological effects, efficiency in the presence of this genotype was reduced (p<0,05). The results of treatment were most representative in the areas of OCT 4, OCT 8 and macula (OCT 3) – among carriers of allele A in the OCT 4 zone, the chance of resistance to treatment was 3.1 times (OR=3.1; 95% SI 1,686 - 5.7) higher than in carriers of the G allele, and in the zone of OCT 8 in patients from the study group the risk of ineffectiveness of therapy was 2.81 times (OR=2.81; 95% CI 1.56 - 5.059) higher than in the corresponding zone of the G allele carriers. This suggests a lack of clinical efficacy in individuals carrying the mutant A allele, and the need to identify the status of polymorphisms for prognostic assessment of treatment efficacy.
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