Genetics in Diabetic Retinopathy: Current Concepts and New Insights

Abstract

There is emerging evidence which indicates the essential role of genetic factors in the development of diabetic retinopathy (DR). In this regard it should be highlighted that genetic factors account for 25-50% of the risk of developing DR. Therefore, the use of genetic analysis to identify those diabetic patients most prone to developing DR might be useful in designing a more individualized treatment. In this regard, there are three main research strategies: candidate gene studies, linkage studies and Genome-Wide Association Studies (GWAS). In the candidate gene approach, several genes encoding proteins closely related to DR development have been analyzed. The linkage studies analyze shared alleles among family members with DR under the assumption that these predispose to a more aggressive development of DR. Finally, Genome-Wide Association Studies (GWAS) are a new tool involving a massive evaluation of single nucleotide polymorphisms (SNP) in large samples. In this review the available information using these three methodologies is critically analyzed. A genetic approach in order to identify new candidates in the pathogenesis of DR would permit us to design more targeted therapeutic strategies in order to decrease this devastating complication of diabetes. Basic researchers, ophthalmologists, diabetologists and geneticists should work together in order to gain new insights into this issue.

A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression

“…In line with this, VEGFA expression is induced by hyperglycemia and hypoxia1, two hallmarks of diabetic complications, whereas levels of VEGFA are markedly increased in the vitreous of diabetic patients with active PDR6. However, despite many investigations, the underlying etiology of DR is largely unknown7, although genetic factors may contribute to both the occurrence and severity of this disease8. In this regard, the heritability estimates reported seem to be as high as 27% for NPDR and 50% for PDR910.…”

“…In this regard, the heritability estimates reported seem to be as high as 27% for NPDR and 50% for PDR910. Investigations using different approaches, including the more recent genome-wide association studies (GWAS), have been conducted, but success in identifying the genetic variants involved in DR has been limited811.…”

Candidate gene studies of diabetic retinopathy in human

“…VEGF is activated by microvascular changes induced by hypoxia during DM and also by hyperglycaemia [120]. Activation of VEGF leads to the destruction of the blood retinal barrier (BRB), the development of diabetic macular oedema and neovascularization typical for PDR.…”

Nanoparticle-based technologies for retinal gene therapy

“…Of the latter, the most prevalent include diabetic retinopathy and age-related macular degeneration, in which the genetic component is not necessarily causative, and mutations in associated genes only contribute to risk of developing the disease (reviewed in [3, 4]). On the other hand, most monogenic hereditary diseases can be traced in patients’ genealogical pedigrees, and whole genome sequencing of samples from the patient and family members accelerates the identification of causal mutations and subsequent evaluation of disease mechanisms.…”