Genetic variability in the RAGE gene and sRAGE levels do not predict diabetes-related morbidity and mortality
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| Year of publication | 2012 |
| Type | Conference abstract |
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| Description | Background and aims: Activation of the Receptor for Advanced Glycation Endproducts (RAGE) by its ligands triggers intracellular signal cascade leading to proinflammatory shift of cellular phenotype. Sustained RAGE activation as seen in diabetes causes cellular dysfunction participating in the pathogenesis of micro- and macrovascular diabetic complications. Using cross-sectional association study design we have previously identified RAGE “risk” haplotype (for diabetic nephropathy (DN) comprised of minor alleles of htSNPs -429T/C (rs1800625) and 2184A/G (rs3134940). Endothelial cells produce truncated soluble RAGE (sRAGE) that supposedly acts as natural competitive inhibitor of RAGE signalling, however out previous cross-sectional data identified sRAGE levels as a function of GFR rather that compensatory protective mechanism. Using follow-up data from prospective study of diabetic population of South Moravia region of Czech Republic the aim of our study was to analyse genetic data related to the RAGE gene and sRAGE levels as potential biomarkers of adverse outcomes of diabetes. Materials and methods: Study comprised a total of 412 diabetic subject with variable stage of DN (i.e. normoalbuminuria (n=75), persist. microalbuminuria (n=96), proteinuria (n=147) and ESRD (n=94)) prospectively followed for a median of 39 [IQR 21 - 59] months. Following end-points were considered: [1] progression of DN by stage, [2] major cardiovascular event (MCVE, non-fatal myocardial infarction or stroke, limb amputation) and [3] all-cause mortality (ACM). Genotyping of RAGE variants (-429T/C, -374T/A, G82S, 1704G/T, 2184A/G, 2245G/A) was performed by methods based on PCR. Baseline serum concentration of sRAGE were measured using ELISA (plasma samples were available in 214 subjects). Software PHASE was used to estimate population haplotype frequencies. Kaplan Meier time-to-event analysis was carried out to ascertain contribution of studied parameters to the three endpoints. Results: Comparison of allele and genotype frequencies of RAGE variants between subjects with and without DN revealed differences only in allele and genotype frequencies of 2245G/A polymorphism (chi-square test, P=0.0047 and 0.0148, respectively). Frequencies of the RAGE risk haplotype did not differ significantly (P>0.05). Cumulative incidence of progression of DN was 22.9 %, MCVE 8.2 %, and ACM 19.8 %. No significant effects were ascertained for the carrier state of RAGE genotypes/haplotypes and progression of DN, MCVE and ACM (all P>0.05, log-rank test). For analogous analysis with sRAGE level, subjects were divided into two groups according to the median of sRAGE. We did not identify any significant difference in studied end-points between the groups (all P>0.05, log-rank test). Conclusion: Our results indicate that neither genetic variation in RAGE gene nor sRAGE level could be used as a robust predictor of diabetes-associated morbidity or mortality. |
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