Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism

Abstract

The receptor for advanced glycation end-products (RAGE) is a cell surface transmembrane multiligand receptor, encoded by the AGER gene. RAGE presents many transcripts, is expressed mainly in the lung, and involves multiple pathways (such as NFκB, Akt, p38, and MAP kinases) that initiate and perpetuate an unfavorable proinflammatory state. Due to these numerous functional activities, RAGE is implicated in multiple diseases. AGER is a highly polymorphic gene, with polymorphisms or SNP (single-nucleotide polymorphism) that could be responsible or co-responsible for disease development. This review was designed to shed light on the pathological implications of AGER polymorphisms. Five polymorphisms are described: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion. The rs2070600 SNP may be associated with the development of human autoimmune disease, diabetes complications, cancer, and lung diseases such as chronic obstructive pulmonary disease and acute respiratory distress syndrome. The rs1800624 SNP involves AGER gene regulation and may be related to reduced risk of heart disease, cancer, Crohn’s disease, and type 1 diabetes complications. The rs1800625 SNP may be associated with the development of diabetic retinopathy, cancer, and lupus but may be protective against cardiovascular risk. The rs184003 SNP seems related to coronary artery disease, breast cancer, and diabetes. The 63 bp deletion may be associated with reduced survival from heart diseases during diabetic nephropathy. Here, these potential associations between AGER polymorphisms and the development of diseases are discussed, as there have been conflicting findings on the pathological impact of AGER SNPs in the literature. These contradictory results might be explained by distinct AGER SNP frequencies depending on ethnicity.

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

“…AT1 cells are the dominant population in alveoli and mediate gas exchange and, when injured or dying, can release proliferation and regenerative signals (Desai et al, 2014). The alveolar signature we detected in the cancer cells at RD includes increased expression of both AT1-and AT2-associated genes ( Supplemental Table 2), including AQP4, SFTPB/C/D, CLDN18, FOXA2, NKX2-1 and PGC for AT2 cells (Desai et al, 2014;Liu et al, 2003;Nabhan et al, 2018;Wade et al, 2006;Xu et al, 2016;Zhou et al, 2018) and AGER and HOPX for AT1 cells (Nabhan et al, 2018a;Serveaux-Dancer et al, 2019) Figure 3B). Additional analysis demonstrated that the alveolar cell state we identified in cancer cells was not derived from misannotated non-cancer alveolar cells within our cancer cell populations (Supplemental Figure 3C).…”

Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models

“…Multiple SNPs of the AGER gene have been described; among the most common include the following: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion (114,115). The rs2070600 represents the nucleotide change 244G>A and at the amino acid level, Gly82Ser (114).…”

“…Multiple SNPs of the AGER gene have been described; among the most common include the following: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion (114,115). The rs2070600 represents the nucleotide change 244G>A and at the amino acid level, Gly82Ser (114). This AGER SNP was of particular interest on account of the fact that the Gly82Ser is within the V-type Ig domain, that is, the extracellular domain encompassing much of the ligand binding capacity (116).…”

“…Other SNPs, specifically, rs1800624 (-388T>A), rs1800625 (-442T>C), and rs1051993 (-1435G>T); and a 63 base pair deletion (-421_-359) reflect promoter variants and rs184003 (822+49G>T) affects intron 7-8 (114).…”

“…Review of the literature suggests that the links of AGER SNPs to cardiovascular disease (CVD) may be dependent on ethnicity (114). For example, extensive studies in the Chinese Han population suggested that the rs2070600 SNP was significantly associated with increased risk of all-cause mortality and acute myocardial infarction (MI) (118).…”