Gene Polymorphisms of the Receptor for Advanced Glycation End Products and Its Role in the AGE-RAGE Pathway and Inflammation



Shaw, Gladys

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Advanced glycation end products (AGEs) are cross-linked, non-degradable aggregates of proteins, lipids and nucleic acids produced during aging and many aging-associated chronic diseases. Additionally, the receptor for advanced glycation end products (RAGE) is an important receptor in the pro-inflammatory pathway. Clinically, metabolic diseases associated with inflammation, such as diabetes, non-alcoholic fatty liver disease (NAFLD), and obesity, may be exacerbated by a) Varying levels of RAGE isoforms; b) Polymorphisms in AGER, the gene encoding RAGE, may influence ligand-receptor interaction or RAGE levels; c) Variations in concentration of RAGE’s ligand, advanced glycation end products (AGE). These variations will alter inflammatory milieu within the human body. TaqMan qPCR was employed in genotyping of 4 inflammation-related SNPs located within the AGER gene (T-429C, T-374A, Gly82Ser/G344A, and G1704T) in 340 obese patients. ELISA assays were used in the analysis of RAGE protein isoforms in the serum of these patients. Statistic-based haplotype and individual genotype analysis was used to determine whether a particular genotype/haplotype of the AGER locus produces significantly different levels of RAGE protein in those with varying levels of non-alcoholic fatty liver disease. Correlations between liver histopathology and frequencies of specific AGER haplotypes, T-429 – A-374 – Gly82/G344 – G1704 and T-429 – A-374 – Gly82/G344 – T1704 were detected. Additionally, a significant difference between AGE levels in patient sera were discovered between the “mild abnormality of liver parenchyma” and the “no disease” group, yet this significance was not maintained when patients were separated based upon their diabetes status. This work can be used as a foundation for future studies aiming to untangle the complex nature of AGE-RAGE interactions and inflammation in morbidly obese populations.