Soluble receptor for advanced glycation end products (sRAGE) and asthma: Mendelian randomisation study.
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ABSTRACT:
SUBMITTER: Raita Y
PROVIDER: S-EPMC8249337 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor involved in various human diseases, as it binds to numerous molecules and proteins that modulate the activity of other proteins. Elucidating the three-dimensional structure of this receptor is therefore most important for understanding its function during activation and cellular signaling. The major alternative splice product of RAGE comprises its extracellular region that occurs as a soluble protein (sRAGE). Although the structures of sRAGE domains were available, their assembly into the functional full-length protein remained unknown. We observed that the protein has concentration-dependent oligomerization behavior, and this is also mediated by the presence of Ca(2+) ions. Moreover, using synchrotron small angle x-ray scattering, the solution structure of human sRAGE was determined in the monomeric and dimeric forms. The model for the monomer displays a J-like shape, whereas the dimer is formed through the association of the two N-terminal domains and has an elongated structure. These results provide insights into the assembly of the RAGE homodimer, which is essential for signal transduction, and the sRAGE:RAGE heterodimer that leads to blockage of the receptor signaling, paving the way for the design of therapeutic strategies for a large number of different pathologies.
| S-EPMC3199498 | biostudies-literature
Project description:The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface proteins that has been implicated as a progression factor in a number of pathologic conditions from chronic inflammation to cancer to Alzheimer's disease. In such conditions, RAGE acts to facilitate pathogenic processes. Its secreted isoform, soluble RAGE or sRAGE, has the ability to prevent RAGE signaling by acting as a decoy. sRAGE has been used successfully in animal models of a range of diseases to antagonize RAGE-mediated pathologic processes. In humans, sRAGE results from alternative splicing of RAGE mRNA. This study was aimed to determine whether the same holds true for mouse sRAGE and, in addition, to biochemically characterize mouse sRAGE. The biochemical characteristics examined include glycosylation and disulfide patterns. In addition, sRAGE was found to bind heparin, which may mediate its distribution in the extracellular matrix and cell surfaces of tissues. Finally, our data indicated that sRAGE in the mouse is likely produced by carboxyl-terminal truncation, in contrast to the alternative splicing mechanism reported in humans.
| S-EPMC1868562 | biostudies-literature
Project description:BackgroundSoluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.MethodssRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).ResultsLower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.ConclusionsLower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
| S-EPMC8076883 | biostudies-literature
Project description:ObjectivesThe soluble receptor for advanced glycation end products (sRAGE) has been implicated in the development of diabetes-related vascular complications, but the variability of concentrations of sRAGE in the blood is unknown. The objective of this study was to characterize within-person three-year variability of plasma levels of sRAGE.Design and methodsWe measured sRAGE in plasma samples from 179 men and women in the community-based Atherosclerosis Risk in Communities (ARIC) Study at two time points, three years apart. We calculated correlation coefficients and the within-person coefficient of variation (CVw) to characterize variability in sRAGE. We compared these estimates to total cholesterol and white blood cell count (WBC) in the same participants.ResultsMean sRAGE concentrations at the two time points (mean time between measurements = 2.9 years) were 1096.2 pg/mL and 990.2 pg/mL, respectively (mean difference = -106.0 pg/mL, p-value < 0.001). The Pearson's correlation was 0.78 (Spearman's, 0.73). The intra-class correlation coefficient was 0.76 and the CVw was 26.6%. Compared to sRAGE, Pearson's and Spearman's correlations for total cholesterol (0.76 and 0.77) and white blood cell count (0.61 and 0.72) were similar, although CVw for both was lower (8.7% for cholesterol, 15.6% for WBC). Less than 4% of participants' values changed substantially (50% or greater) over the three-year interval.ConclusionsWe observed that sRAGE concentrations remained relatively stable over three years. Our findings suggest that a single measure of circulating sRAGE tracks well in a community-based population and could be a useful measure in clinical and epidemiologic studies of long-term risk.
| S-EPMC4263345 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis, better monitoring, and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury, and is associated with inflammation, cell proliferation and migration in PAH. For the adult cohort, we recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH) and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3332 ± 321.6 pg/mL) versus controls (1766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II+III PAH versus controls (p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults, but were similar in PH (n = 10) and non-PH controls (n = 10). Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.
| S-EPMC8395319 | biostudies-literature
Project description:ObjectiveIncreased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE.DesignProspective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset.SettingAntenatal clinics.PopulationPregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21).MethodsMaternal serum levels of sRAGE (total circulating pool), N(?)-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays.Main outcome measuresSerum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-).ResultsIn DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates.ConclusionsIn the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.
| S-EPMC3980671 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is characterized by abnormal action of the immune system and a state of chronic inflammation. The disease can cause life-threatening complications. Neoepitopes arising from interdependent glycation and oxidation processes might be an element of SLE pathology. The groups included in the study were 31 female SLE patients and 26 healthy female volunteers (the control group). Blood serum samples were obtained to evaluate concentrations of advanced glycation end-products (AGEs), carboxymethyllysine (CML), carboxyethyllysine (CEL), pentosidine, and a soluble form of the receptor for advanced glycation end-products (sRAGE). Compared to a healthy control group, the SLE patients exhibited a higher concentration of AGEs and a lower concentration of sRAGE in serum. There were no statistically significant differences in serum CML, CEL, and pentosidine concentrations between the groups. Therefore, SLE patients could be at risk of intensified glycation process and activation of the proinflammatory receptor for advanced glycation end-products (RAGE), which could potentially worsen the disease course; however, it is not clear which compounds contribute to the increased concentration of AGEs in the blood. Additionally, information about the cigarette smoking and alcohol consumption of the study participants was obtained.
| S-EPMC8700453 | biostudies-literature
Project description:BackgroundCoronavirus disease 2019 (COVID-19) is a new health problem discovered in 2019 thus requires biomarkers that can detect early tissue damage. Soluble receptor for advanced glycation end-products (sRAGE) is a biomarker that can be used to identify early lung damage.ObjectiveAnalyzing the association of serum sRAGE on COVID-19 severity.MethodsThis study employed a cross-sectional design with a consecutive sampling method. It was conducted from May 2020-October 2021. The number of participants in this study was 145 participants which were divided into 2 groups (non-severe = 47 and severe = 98). Association of sRAGE serum on COVID-19 severity was analyzed using the chi-square test, Fisher's exact test, independence t-test, Mann Withney test, and Spearman's rank test with p-value <0.05.ResultsThe results of blood analysis showed several blood components such as leukocytes (9896.51 ± 4949.64/μL; z = 2.431; p = 0.015), lymphocytes (13.55 ± 8.48%; z = 2.256; p = 0.024), neutrophils (78.91 ± 10.50%; z = 2.464; p = 0.014), procalcitonin (0.92 ± 3.22 ng/mL; z = 3.323; p = 0.001), CRP (8.59 ± 7.62 mg/L; z = 2.114; p = 0.034), D-dimer (4360.29 ± 7797.81 ng/mL; z = 2.186; p = 0.029), and fibrinogen (474.58 ± 168.90 mg/dL; t = 0.383; p = 0.703). There was a significant comparison in serum sRAGE values in the non-severe group (0.78 [0.63-1.00] ng/mL) and severe group (1.47 [0.97-2.25] ng/mL; r = 7.154; p <0.001). There was a significant association between serum sRAGE and COVID-19 severity (r = 0.598; p <0.001). The cut-off value for serum sRAGE between the severe and non-severe groups was 0.985 ng/mL. This study obtained sensitivity of 73.5%, specificity of 74.5% OR 8.077 and AUC 0.868 95% CI.ConclusionThere is a significant association between serum sRAGE and COVID-19 severity and there is also a significant difference in serum sRAGE in the two groups.
| S-EPMC8800495 | biostudies-literature
Project description:BackgroundAlthough bronchiolitis contributes to substantial acute (e.g., intensive care use) and chronic (e.g., recurrent wheeze and infections) morbidities in young children, the pathobiology remains uncertain. We examined relations of serum soluble receptor for advanced glycation end-products (sRAGE) with acute and chronic morbidities of bronchiolitis and whether the effect of serum sRAGE on development of recurrent wheeze is mediated through acute severity.MethodsA multi-center, multi-year, prospective cohort study of infants hospitalized for bronchiolitis was analyzed. We measured serum sRAGE level at acute hospitalization and examined its association with intensive care use (use of mechanical ventilation and/or admission to intensive care unit) and development of recurrent wheeze by age 3 years. We performed causal mediation analysis to estimate indirect (mediation) and direct effects of sRAGE on recurrent wheeze.ResultsIn 886 infants with bronchiolitis, median age was 2.9 months. Overall, 15% underwent intensive care and 32% developed recurrent wheeze by age 3 years. In the multivariable model adjusting for 11 confounders, higher presenting sRAGE level was associated with significantly lower risk of intensive care use (OR for each one-log increment, 0.39; 95%CI 0.16-0.91; P=0.03) and significantly lower rate of recurrent wheeze (HR 0.58; 95%CI 0.36-0.94; P=0.03). In mediation analysis, the direct effect was significant (HR 0.60; 95%CI 0.37-0.97; P=0.04) while the indirect effect was not (P=0.30).ConclusionsSerum sRAGE levels were inversely associated with acute and chronic morbidities of bronchiolitis. Effect of sRAGE on development of recurrent wheeze is potentially driven through pathways other than acute severity of bronchiolitis.
| S-EPMC8563181 | biostudies-literature
Project description:BackgroundInflammation is key in the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) - a common progressive liver disease. The soluble receptor for advanced glycation end products (sRAGE) attenuates inflammatory signaling; low levels of sRAGE are correlated with increased inflammation.AimWe sought to describe associations between sRAGE and NAFLD.MethodsWe conducted a cross-sectional analysis of 1088 Atherosclerosis Risk in Communities (ARIC) Study participants and used logistic regression to investigate the associations between sRAGE and NAFLD defined by elevated liver enzymes and fibrosis score.ResultsIn this community-based sample (n = 1,088, mean age 56 years, 61% female, 78% Caucasian), persons in the lowest vs. highest quartile of sRAGE had significantly higher odds of elevated ALT (OR 2.82, 95% CI 1.18-6.76) but not elevated AST (OR 1.16, 95% CI 0.45-2.99); persons in the lowest vs. highest quartile had significantly lower odds of elevated FIB-4 index (OR 0.56, 95% CI 0.37-0.84).ConclusionsWe found an inverse cross-sectional association between sRAGE and liver inflammation; this is consistent with prior studies linking low sRAGE to inflammatory states. However, we observed a direct association between sRAGE and fibrosis. Our findings suggest that sRAGE is dynamic in NAFLD and patterns may vary with different stages of disease.
| S-EPMC8238805 | biostudies-literature