Studio di polimorfismi in geni coinvolti in patologie oculari angioproliferative
Year: 2011
Type: dissertation
Study design: Observational Study
Abstract: The ocular angioproliferative diseases are multifactorial diseases, characterized by a progressive degeneration of cells in the macular region of the retina which permit distinct and central vision. This means that people with these diseases gradually lose their "high definition" vision guaranteed by the macula. The most frequent cause of macular degeneration is the age-related macular degeneration (AMD), which usually affects people older than 50 years and is the leading cause of legal blindness in the elderly population. The macula may also be affected by pathology in diabetic retinopathy (DR); the presence of exudates and accumulation of fluid leaking from the capillaries, causing a condition called macular edema, are the most common cause of loss of visual function in diabetic patients. VEGF (Vascular Endothelial Growth Factor) and the receptor KDR (kinase insert domain receptor) regulate angiogenesis and therefore considered important factors involved in the pathological process that leads to the onset of ocular angioproliferative disease. In the first part, an association study between polymorphisms in the VEGF and its receptor KDR genes and onset of ocular diseases such as AMD and DR, has been performed. For this purpose we analyzed 16 polymorphisms (11 in the VEGF gene and 5 on the gene KDR) in a population of 226 patients with AMD, 177 patients with diabetic retinopathy and a control population of 240 healthy subjects. All the SNPs were analyzed by GenomeLab SNPStream DNA microarray technology (Beckman Coulter) that allows a large-scale genotyping. The results obtained in this first part showed a strong association between some polymorphisms of VEGF-A and, for the first time, KDR with susceptibility to the onset of ocular angioproliferative disease. A recent study showed that the CCR3 (CC chemokine receptor type 3) and corresponding ligands eotaxin 1,2,3 are expressed only in the endothelial cells lining the abnormal blood vessels of CNV from people with wet AMD and not in choroidal endothelium from people without AMD, or from those with dry AMD or other types of choroidal or retinal disorder. Therefore, in the second part of the study we have analyzed, for the first time, if single nucleotide polymorphisms in the genes CCR3 and eotaxin 1 (CCL11), eotaxin 2 (CCL24), eotaxin 3 (CCL26) are associated with the onset of AMD and DR. For this purpose we selected 46 polymorphisms (14 in the CCR3 gene, 8 in the gene CCL11, 4 in the CCL26 gene, 11 in the VEGF-A gene and 4 in the KDR gene) in 283 patients with AMD, 175 patients with diabetic retinopathy and control population of 262 healthy subjects. Genotyping analysis was performed using the Illumina BeadXpress, a high-throughput, dual-color laser detection system that enables scanning of a broad range of multiplexed assays developed using the VeraCode digital microbead technology. This technology was also used to confirm the association of VEGF-KDR pathway with AMD and DR extending the number of SNPs studied in these two genes. The analysis of allele and genotype frequencies of the CCR3 and eotaxins genes between groups of patients AMD and DR and the control group did not show any statistically significant difference. Instead, we again confirmed the importance of VEGF / KDR pathway, expanding the current knowledge on the role of this growth factor in pathophysiology of these diseases and demonstrating a genetic contribution in susceptibility to the onset of AMD and DR. The in-depth knowledge of these mechanisms could provide the basis to determine the risk of developing the disease and understand its entirety to allow the identification and synthesis of new drugs. In fact, carriers of risk alleles or non-risk may respond differently to therapy or may require different amounts of anti-VEGF (currently used in the treatment of these diseases) to increase its effectiveness.
Author: Genny Buson
Language: Italian
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2274518366