Association of Four Genetic Polymorphisms of AGER and Its Circulating Forms with Coronary Artery Disease: A Meta-Analysis

Abstract

BackgroundConsiderable efforts have been devoted to evaluating the association of the receptor for advanced glycation end-products (gene AGER and protein: RAGE) genetic variants to coronary artery disease (CAD); the results, however, are often irreproducible. To generate more information, we sought to explore four common polymorphisms of AGER and its circulating forms associated with the risk of CAD via a meta-analysis.Methodology/Principal FindingsArticles were identified by searching PubMed, EMBASE, Wanfang and CNKI databases before March 2013. Qualified articles had case-control designs and investigated AGER four polymorphisms (T-429C, T-374A, Gly82Ser, G1704A) or circulating soluble RAGE (sRAGE) or endogenous secretory RAGE (esRAGE) levels associated with CAD. Twenty-seven articles involving 39 independent groups fulfilled the predefined criteria. Overall, no significance was observed for all examined polymorphisms under allelic and dominant models. When restricting groups to CAD patients with diabetes mellitus or renal disease, deviations of risk estimates from the unity were stronger than overall estimates for all polymorphisms except for G1704A due to limited available studies. For example, under dominant model, having -429C allele increased the odds of developing CAD in diabetic patients by 1.22-fold (95% confidence interval (95% CI) 0.99–1.51; P = 0.06; I 2 = 6.7%) compared with that of overall estimate of 1.15-fold (95% CI: 0.97–1.36; P = 0.111; I 2 = 18.0%). Circulating sRAGE levels were non-significantly lower in CAD patients than in controls, whereas this reduction was totally and significantly reversed in CAD patients with diabetes mellitus (weighted mean difference: 185.71 pg/ml; 95% CI: 106.82 to 264.61 pg/ml). Circulating esRAGE levels were remarkably lower in CAD patients, as well as in subgroups with or without diabetes mellitus and without renal disease.ConclusionsOur findings demonstrated that association of AGER genetic polymorphisms with CAD was potentiated in patients with diabetes mellitus or renal disease. Practically, circulating esRAGE might be a powerful negative predictor for the development of CAD.

Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study

“…Our results demonstrating the lack of a significant effect of AGER variation on cardiovascular outcomes in whites are consistent with most prior case-control studies [ 29 , 30 ] and extend these findings using a prospective cohort design which addresses confounding and selection bias more fully. While some case-control studies have identified associations between AGER SNPs and myocardial infarction and stroke [ 31 ] and prevalent coronary heart disease based on angiographic evidence of stenosis >50% [ 32 ], two recent meta-analyses including over 25 case-control studies (maximum N for single SNP = 7,111) [ 29 ] did not find a consistent association between AGER polymorphisms and coronary heart disease (odds ratios from meta-analyses ranged from 0.97 to 1.16 with P >0.05) [ 29 , 30 ]. It is important to note, however, that rs2070600 has been associated with other diseases, including type 1 diabetes [ 33 ], chronic obstructive pulmonary disease [ 26 ], schizophrenia [ 34 ], and Alzheimer’s Disease [ 35 ].…”

Clinical and Biological Predictors of Plasma Levels of Soluble RAGE in Critically Ill Patients: Secondary Analysis of a Prospective Multicenter Observational Study

“…There has been extensive research on sRAGE and esRAGE in patients with type 2 diabetes, and lower levels of both sRAGE and esRAGE may be markers of poor glycemic control [ 56 ] and of increased risk of microvascular complications [ 57 ]. However, whether elevated sRAGE is associated with a higher or lower risk of cardiovascular risk during diabetes remains controversial [ 53 , 56 ], and contradictory findings from previous studies may be explained by rather small sample sizes that may have hampered the detection of clinically relevant effect sizes [ 58 ]. In addition, studies of RAGE isoforms in health and diseases should also ideally integrate the roles of ethnicity [ 59 ] and of RAGE gene variants [ 60 ].…”

Association of RAGE gene Gly82Ser polymorphism with coronary artery disease and ischemic stroke

“…Although several relevant meta-analyses have analyzed the relationship between the Gly82Ser polymorphism and CAD susceptibility, [42,43] there are some differences. More eligible studies were included in our study and 5 genetic models gave us a comprehensive understanding of the relationship between the Gly82Ser polymorphism and susceptibility to CAD.…”