Single nucleotide variants of receptor for advanced glycation end-products (AGER) gene: is it a new opening in the risk assessment of diabetic retinopathy?-a review

Abstract

Background: Diabetic retinopathy (DR) is a common microvascular complication of diabetes. There is strong evidence suggesting that DR has an inheritable component. The interaction between advanced glycation end products (AGEs) and their receptor is integral in the pathogenesis of diabetic retinopathy and its various complications, retinopathy being one of them.

Overview and methodology: This review discusses the existing literature on the association between single nucleotide variants (SNV) of AGER gene and the risk of DR. It also discusses the current understanding of the AGE-AGER pathway in diabetic retinopathy. Through our article we have tried to consolidate all the available information about these SNVs associated with diabetic retinopathy in a succinct tabular form. Additionally, a current understanding of the AGE-AGER interaction and its deleterious effects on the cells of the retina has been discussed in detail to provide comprehensive information about the topic to the reader. A literature review was performed on PubMed, Cochrane Library, and Google Scholar for studies to find existing literature on the association between AGER gene SNVs and the risk, progression and severity of developing DR. This article will encourage scientific communication and discussion about possibly devising genetic markers for an important cause of blindness both in developed and developing countries, i.e., diabetic retinopathy.

Result: Based on genetic studies done in Indian and Chinese population G82S(rs2070600) was positively associated with Diabetic Retinopathy. Patients of diabetic retinopathy in Caucasian population had -T374A(rs1800624) polymorphism. + 20T/A was found to be associated with the disease in a study done in UK. Association with G1704T(rs184003) was seen in Chinese and Malaysian population. A Chinese study found its association with CYB242T. -T429C(rs1800625) SNV was not associated with DR in any of the studies. G2245A(rs55640627) was positively associated with the disease process in Malaysian population. It was not associated in Malaysian and Chinese population. Promoter variant rs1051993 has also been found to a susceptible SNV in the Chinese population.

Conclusion: While providing a comprehensive review of the existing information, we would like to emphasize on a large, multi-centric, trial with a much larger and varied population base to definitely determine these single nucleotide variants predisposing diabetic individuals.

Keywords: Gene marker; Receptor for advanced glycation end products (AGER), single nucleotide variants (SNV), diabetic retinopathy; Risk factor.

Fig. 1

Hyperglycemia-mediated activation of various biochemical pathways. Reactive oxygen species generated due to hyperglycemia increase the transcription of various downstream signalling pathways by damaging the structure of DNA. This halts the normal pathway of glycolysis so that its substrates are diverted to other biochemical pathways. Glyceraldehyde 3 phosphate isomerizes to dihydroxyacetone phosphate (DHAP) that increases the production of advanced glycation end products. Activation of the hexosaminase pathway causes increased o glycosylation of glycolytic substrates. Activation of pyruvate kinase pathway, especially pyruvate kinase beta and NFAT pathway upregulation causes further activation of cytokines, chemokines, and interleukins, having deleterious effects on the cells of the retina, all of which is responsible for the changes of diabetic retinopathy. Activation of the polyol pathway leads to increased production of sorbitol and fructose, which are hyperosmotic agents and are implicated in the causation of diabetic cataract. As glyoxylase enzyme is generally overexpressed in the endothelium, AGE accumulation in the vessel wall is less. However, this detoxification system is deficient in people with diabetes, causing more pericyte apoptosis and thus accentuating DR pathology

Fig. 2

Maillard reaction for the formation of advanced glycation products

Fig. 3

Receptor for AGE interacts not only with AGEs but also with other ligands like LPA, CD11, calgranulins, amyloid beta, HGMB1, and S100 protein. The interaction of AGEs with AGER initiates a downstream signalling cascade. The primary mediator for the inflammatory pathway is the ultimate induction of NFkB, which causes oxidative and inflammatory damage. Hyperglycemia associated oxidative ER stress and reactive oxygen species production induce NFkB. This inflammatory and oxidative damage thus caused creates a positive feedback loop causing further AGER activation

Fig. 4

Downstream cascade of various chemokines, cytokines, and inflammatory mediators that causes damage to various retinal cells causing diabetic retinopathy