Soluble receptor and gene polymorphism for AGE: relationship with obesity and cardiovascular risks

Abstract

Background: Obesity in adolescents has quadrupled in the past 30 y. Markers for cardiovascular risks are needed in this population. We hypothesized that soluble receptor for advanced glycation end products (sRAGE) and asymmetric dimethyl arginine (ADMA) can correlate with carotid intimamedia thickness (cIMT), a known index of subclinical atherosclerosis. We also aimed to evaluate the frequency of (Gly82Ser) RAGE gene polymorphism in obese adolescents. Methods: Obese and nonobese adolescents were evaluated in a cross-sectional study for lipid profile, insulin resistance, ADMA, sRAGE, and RAGE gene (Gly 82 Ser) polymorphism. We measured cIMT in all subjects and performed correlation analyses with all markers. results: The study included 50 obese and 40 healthy control adolescents. Compared to controls, obese subjects had less sRAGE (P = 0.02) and greater cIMT (P = 0.006), insulin resistance (P < 0.0001), and ADMA (P < 0.0001). In a multivariate linear regression model, sRAGE was associated with cIMT (β = 0.28, P = 0.04). Both GS and SS genotypes of RAGE were more frequent in obese than controls (P = 0.04). conclusion: Increased ADMA and decreased sRAGE are associated with cardiovascular risks in obese adolescents. The S allele in RAGE gene is more frequently detected with obesity. The role of RAGE gene and mechanisms leading to cardiovascular risks need further studying. c hildhood obesity is an emerging public health challenge with an estimated prevalence of around 20% in western countries (1). Exposure to cardiovascular risk factors in early life, including obesity, may induce changes in the arteries that are associated with the diagnosis of atherosclerosis in adults (2). The measurement of carotid intimamedia thickness (cIMT) is a noninvasive test to detect early alterations in arterial wall and can be a useful screening tool to early assess subclinical manifestations of cardiovascular and metabolic diseases (3). However, there is a desperate need to discover novel biomarkers that can help understand the exact pathophysiology and improve clinical management of cardiovascular diseases associated with obesity in children (4).Asymmetric dimethyl arginine (ADMA) is a competitive inhibitor of endothelial nitric oxide (NO) synthase that reduces the production of NO and therefore might cause endothelial dysfunction. Serum ADMA concentrations are increased in individuals with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus, and chronic renal failure. It has been suggested as a potential risk predictor for cardiovascular events and all-cause cardiovascular mortality in patients with coronary artery disease (5). The relationship between ADMA and cardiovascular complications in children remains unclear.The advanced glycation end products (AGE) and its receptor (RAGE) system is a newly discovered pathway implicated in the pathogenesis of several cardio-metabolic diseases (6). The RAGE is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules and enga...

Correlation among soluble receptors for advanced glycation end-products, soluble vascular adhesion protein-1/semicarbazide-sensitive amine oxidase (sVAP-1) and cardiometabolic risk markers in apparently healthy adolescents: a cross-sectional study

“…even if not accompanied by additional cardiometabolic risk factors such as elevated BP, AIP, and IR, associates with low sRAGE and esRAGE levels. In contrast with our hypothesis, the missing association between sRAGE and/or esRAGE and measures of obesity in some but not all studies [13][14][15][16][17][18][19][20][21][22][39][40][41][42][43] might not be related to the metabolically healthy obese phenotype. Since in non-diabetic adults low sRAGE levels associate independently with a future risk of cardiometabolic diseases and mortality [24], we might presume that a metabolically healthy obese phenotype is far from being a benign condition [44,45].…”

“…The prevalence of this allele in Slovaks is too low (about 4 %) [58] to explain the obesity-associated decline in sRAGE. However, in obese Egyptian adolescents, the prevalence of this mutated allele is much higher (23 %), and the homozygous carriers present significantly lower sRAGE levels in comparison to those carrying the dominant allele [20].…”

“…A RAGE gene may affect the development of insulin resistance or be in linkage disequilibrium with a locus involved in this process [55][56][57][58]. For instance, the minor allele carriers in G82S RAGE polymorphism present low sRAGE levels, insulin resistance and increased levels of pro-inflammatory markers [20,57,58]. The prevalence of this allele in Slovaks is too low (about 4 %) [58] to explain the obesity-associated decline in sRAGE.…”

“…It is presumed that sRAGE levels reflect tissue RAGE expression [12]. However, the majority [13][14][15][16][17][18][19][20], but not all [21][22][23], studies in non-diabetic individuals report lower sRAGE and/or esRAGE levels in obese vs. lean subjects, and/or an inverse relationship between measures of obesity and circulating receptor levels. Reasons underlying these inconsistencies remain unclear but are intriguing in view of the observations that in non-diabetics low sRAGE levels associate with an increased risk of development of metabolic syndrome, diabetes, cardiovascular disease, or death [18,[24][25][26].…”

Glycation & the RAGE axis: targeting signal transduction through DIAPH1

“…Interestingly, recent studies suggest links between the Ser allele of the Gly82Ser AGER polymorphism to obesity risk and that the Ser allele was associated with higher levels of sRAGE in children [43]. A distinct study demonstrated that the Ser allele was more frequently observed in obese adolescents vs. the lean [44]. In that study, however, lower levels of sRAGE were linked to obesity [44].…”