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

Maruthur, Nisa M.; Li, Man; Halushka, Marc K.; Astor, Brad C.; Pankow, James S.; Boerwinkle, Eric; Coresh, Josef; Selvin, Elizabeth; Kao, W. H. Linda

doi:10.1371/journal.pone.0128452

Cited by 23 publications

(40 citation statements)

References 38 publications

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“…However, higher GFR was independently associated with lower total sRAGE levels in Whites. Previous reports indicate that metabolic, lifestyle, and genetic factors explain close to 50% of the variability in total sRAGE [14, 28]. Our fully adjusted model accounted for 24% of the variability in total sRAGE and 14% of the variability in esRAGE.…”

Section: Discussionmentioning

confidence: 75%

“…One study reported similar findings for esRAGE, albeit in a small number (n=25) of Afro-Caribbean patients with type 2 diabetes [10]. A recent genetics analysis showed that variants in the RAGE gene ( AGER ) do not account for racial differences in total sRAGE levels, suggesting that other biological or environmental factors are likely important [14]. Given that low sRAGE levels have been associated with type 2 diabetes, cardiovascular disease, and Alzheimer’s disease [15, 16] (i.e., diseases that disproportionately affect Black individuals), it is possible that the observed racial differences in sRAGE may contribute to racial disparities in chronic disease risk.…”

Section: Introductionmentioning

confidence: 81%

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Racial differences in circulating levels of the soluble receptor for advanced glycation endproducts in middle-aged and older adults

et al. 2017

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Background Low levels of the soluble receptor for advanced glycation endproducts (sRAGE) have been implicated in a number of chronic diseases. Previous studies indicate that sRAGE levels are ~30% lower in Blacks compared to Whites. However, the reasons for these differences are unclear. Purpose We aimed to identify predictors of circulating sRAGE biomarkers among Black and White adults at high cardiac risk. Methods Serum levels of total sRAGE, endogenous secretory RAGE (esRAGE), carboxymethyl-lysine (CML, a major RAGE ligand), and their ratios were measured in 99 Blacks and 454 Whites. Results Blacks had a more adverse cardiovascular risk profile, as well as lower median levels of total sRAGE (972 vs. 1564 pg/ml) and esRAGE (474 vs. 710 pg/ml) compared to Whites (p<0.0001). In addition, the proportion of esRAGE was higher in Blacks (47% vs. 44%, p=0.02), as were the CML/total sRAGE (0.89 vs. 0.56 ng/pg) and CML/esRAGE (1.72 vs. 1.20 ng/pg) ratios (p<0.0001). Racial differences persisted after adjustment for key covariates including age, gender, tobacco use, comorbidities, BMI, blood pressure, glucose, insulin, triglycerides, C-reactive protein, and renal function (p<0.05). Race alone accounted for nearly half of the variability in total sRAGE levels (10.6%; model explained 23.9%). In stratified analyses, gender and heart rate were independently associated with total sRAGE and esRAGE in Whites, while CML and C-reactive protein were associated with total sRAGE in Blacks. Conclusions We identified several independent predictors of sRAGE biomarkers. Notably, Black race was associated with an adverse AGE/RAGE profile, including lower sRAGE and higher CML/sRAGE ratios.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 81%

Racial differences in circulating levels of the soluble receptor for advanced glycation endproducts in middle-aged and older adults

et al. 2017

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“…This receptor is expressed as membrane-bound (mRAGE) and soluble (sRAGE) forms; the latter is produced primarily by shedding of mRAGE (Raucci et al, 2008) and is thought to function as a ‘decoy’ receptor, preventing RAGE ligands from interacting with mRAGE, which would normally trigger inflammation (Schmidt, 2015). Of note, a non-synonymous variant (rs2070600) in the AGER gene (which encodes RAGE) is a strong determinant of serum sRAGE levels (Jang et al, 2007; Maruthur et al, 2015), with the rs2070600:C allele (encoding a Gly at position 82) being associated with increased sRAGE. This same allele is associated with decreased risk of allergic asthma (OR = 0.87, p=0.003 in [Ferreira et al, 2014]).…”

Section: Introductionmentioning

confidence: 99%

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

Arikkatt

Ullah

Short

et al. 2017

eLife

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Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.DOI: http://dx.doi.org/10.7554/eLife.21199.001

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“…Other potential contributors to variation in previous studies include genetic and racial contributions to sRAGE, as sRAGE levels differ by race (14, 17) and 2 variants in the gene that encodes RAGE, AGER (advanced glycosylation end-product specific receptor), explain 26% of the variation in whites and 21.5% of the variation in blacks, but do not explain differences in sRAGE levels by race (24). Thus, inadequate control for race and genetic factors may have contributed to the variable findings in the literature.…”

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confidence: 99%

Cross-sectional Analysis of AGE-CML, sRAGE, and esRAGE with Diabetes and Cardiometabolic Risk Factors in a Community-Based Cohort

et al. 2017

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BACKGROUND Advanced glycation end products (AGEs) and their receptors are regarded as central to the development of diabetic complications, but associations with diabetes and cardiometabolic outcomes in previous studies are mixed. METHODS Using ELISA assays, we measured N(6)-carboxymethyllysine (AGE-CML), soluble receptor for AGEs (sRAGE), and endogenous secreted receptor for AGEs (esRAGE) in 1874 participants from the Atherosclerosis Risk in Communities study. We conducted a cross-sectional analysis to evaluate associations of these biomarkers with demographics, diabetes, hyperglycemia, cardiometabolic measures, and genetic variants in the gene encoding RAGE, AGER (advanced glycosylation end-product specific receptor). RESULTS After adjustment for demographics and body mass index (BMI), there were no significant differences in AGE-CML, sRAGE, or esRAGE by diabetes or hemoglobin A1c. Black race and AGER genetic variants were strongly associated with lower sRAGE and esRAGE even after adjustment [percent difference (95% CI) in black vs whites in sRAGE: −29.17 (−34.86 to −23.48), esRAGE: −26.97 (−33.11 to −20.84); with rs2070600 in sRAGE: −30.13 (−40.98 to −19.29), and esRAGE: −30.32 (−42.42 to −18.21); with rs2071288 in sRAGE: −20.03 (−34.87 to −5.18), and esRAGE: −37.70 (−55.75 to −19.65)]. Estimated glomerular filtration rate and albuminuria significantly correlated with sRAGE and esRAGE. BMI and C-reactive protein significantly negatively correlated with AGE-CML, sRAGE, and esRAGE. AGE-CML was modestly correlated with fructosamine and glycated albumin. CONCLUSIONS AGE-CML, sRAGE, and esRAGE were more related to genetic, kidney, and inflammatory measures than to diabetes in this community-based population. Our results suggest that, when measured by ELISA, these biomarkers lack specificity and are of limited value in evaluating the role of these compounds in diabetes.

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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

Cited by 23 publications

References 38 publications

Racial differences in circulating levels of the soluble receptor for advanced glycation endproducts in middle-aged and older adults

Racial differences in circulating levels of the soluble receptor for advanced glycation endproducts in middle-aged and older adults

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

Cross-sectional Analysis of AGE-CML, sRAGE, and esRAGE with Diabetes and Cardiometabolic Risk Factors in a Community-Based Cohort

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