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GDF-15, Galectin 3, Soluble ST2, and Risk of Mortality and Cardiovascular Events in CKD.
Tuegel C, Katz R, Alam M, Bhat Z, Bellovich K, de Boer I, Brosius F, Gadegbeku C, Gipson D, Hawkins J, Himmelfarb J, Ju W, Kestenbaum B, Kretzler M, Robinson-Cohen C, Steigerwalt S, Bansal N
(2018) Am J Kidney Dis 72: 519-528
MeSH Terms: Adult, Age Factors, Aged, Biomarkers, Cardiovascular Diseases, Cause of Death, Cohort Studies, Comorbidity, Female, Galectin 3, Growth Differentiation Factor 15, Humans, Interleukin-1 Receptor-Like 1 Protein, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Proportional Hazards Models, Renal Insufficiency, Chronic, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis
Show Abstract · Added January 3, 2019
RATIONALE & OBJECTIVE - Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 (GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD.
STUDY DESIGN - Observational cohort study.
SETTING & PARTICIPANTS - Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study).
EXPOSURES - Circulating GDF-15, Gal-3, and sST2 measured at baseline.
OUTCOMES - Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident.
ANALYTIC APPROACH - Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function.
RESULTS - Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m. Higher GDF-15 (adjusted HR [aHR] per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events.
LIMITATIONS - Event rates for heart failure and atherosclerotic CVD were low.
CONCLUSIONS - Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.
Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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24 MeSH Terms
A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach.
Petersen CP, Meyer AR, De Salvo C, Choi E, Schlegel C, Petersen A, Engevik AC, Prasad N, Levy SE, Peebles RS, Pizarro TT, Goldenring JR
(2018) Gut 67: 805-817
MeSH Terms: Animals, Flow Cytometry, Gastric Mucosa, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Interleukin-1 Receptor-Like 1 Protein, Interleukin-13, Interleukin-33, Macrophages, Metaplasia, Mice, Mice, Inbred C57BL, Mice, Knockout, Parietal Cells, Gastric, Peptides, Real-Time Polymerase Chain Reaction, Receptors, Interleukin, Signal Transduction, Stomach
Show Abstract · Added April 18, 2017
OBJECTIVE - Alternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown.
DESIGN - To determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice.
RESULTS - Profiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss.
CONCLUSIONS - Metaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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19 MeSH Terms
Galectin-3 and Soluble ST2 and Kidney Function Decline in Older Adults: The Cardiovascular Health Study (CHS).
Bansal N, Katz R, Seliger S, DeFilippi C, Sarnak MJ, Delaney JA, Christenson R, de Boer IH, Kestenbaum B, Robinson-Cohen C, Ix JH, Shlipak MG
(2016) Am J Kidney Dis 67: 994-6
MeSH Terms: Aged, Cohort Studies, Creatinine, Cystatin C, Female, Galectin 3, Glomerular Filtration Rate, Humans, Interleukin-1 Receptor-Like 1 Protein, Logistic Models, Longitudinal Studies, Male, Prognosis, Renal Insufficiency, Chronic
Added September 19, 2017
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14 MeSH Terms
IL-33 Signaling Protects from Murine Oxazolone Colitis by Supporting Intestinal Epithelial Function.
Waddell A, Vallance JE, Moore PD, Hummel AT, Wu D, Shanmukhappa SK, Fei L, Washington MK, Minar P, Coburn LA, Nakae S, Wilson KT, Denson LA, Hogan SP, Rosen MJ
(2015) Inflamm Bowel Dis 21: 2737-46
MeSH Terms: Adult, Animals, Child, Colitis, Colitis, Ulcerative, Colon, Cytokines, Goblet Cells, Humans, Immunohistochemistry, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, Intestinal Mucosa, Intestines, Mice, Oxazolone, Real-Time Polymerase Chain Reaction, Receptors, Interleukin, Signal Transduction, Up-Regulation
Show Abstract · Added September 28, 2015
BACKGROUND - IL-33, a member of the IL-1 cytokine family that signals through ST2, is upregulated in ulcerative colitis (UC); however, the role of IL-33 in colitis remains unclear. IL-33 augments type 2 immune responses, which have been implicated in UC pathogenesis. We sought to determine the role of IL-33 signaling in oxazolone (OXA) colitis, a type 2 cytokine-mediated murine model of UC.
METHODS - Colon mucosal IL-33 expression was compared between pediatric and adult UC and non-IBD patients using immunohistochemistry and real-time PCR. OXA colitis was induced in WT, IL-33, and ST2 mice, and histopathology, cytokine levels, and goblet cells were assessed. Transepithelial resistance was measured across IL-33-treated T84 cell monolayers.
RESULTS - Colon mucosal IL-33 was increased in pediatric patients with active UC and in OXA colitis. IL-33 and ST2 OXA mice exhibited increased disease severity compared with WT OXA mice. OXA induced a mixed mucosal cytokine response, but few differences were observed between OXA WT and IL-33 or ST2 mice. Goblet cells were significantly decreased in IL-33 and ST2 OXA compared with WT OXA mice. IL-33 augmented transepithelial resistance in T84 cells, and this effect was blocked by the ERK1/2 inhibitor PD98,059.
CONCLUSIONS - OXA colitis is exacerbated in IL-33 and ST2 mice. Increased mucosal IL-33 in human UC and murine colitis may be a homeostatic response to limit inflammation, potentially through effects on epithelial barrier function. Further investigation of IL-33 protective mechanisms would inform the development of novel therapeutic approaches.
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20 MeSH Terms
Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.
Gaggin HK, Szymonifka J, Bhardwaj A, Belcher A, De Berardinis B, Motiwala S, Wang TJ, Januzzi JL
(2014) JACC Heart Fail 2: 65-72
MeSH Terms: Aged, Biomarkers, Cardiovascular Diseases, Chronic Disease, Female, Growth Differentiation Factor 15, Heart Failure, Humans, Interleukin-1 Receptor-Like 1 Protein, Male, Middle Aged, Natriuretic Peptide, Brain, Peptide Fragments, Prospective Studies, Receptors, Cell Surface, Risk Assessment, Treatment Outcome, Troponin T, Ventricular Dysfunction, Left, Ventricular Remodeling
Show Abstract · Added April 15, 2014
OBJECTIVES - This analysis aimed to perform a head-to-head comparison of 3 of the promising biomarkers of cardiovascular (CV) outcomes in heart failure (HF)-soluble ST2 (sST2), growth differentiation factor (GDF)-15, and highly-sensitive troponin T (hsTnT)-and to evaluate the role of serial measurement of these biomarkers in patients with chronic HF.
BACKGROUND - sST2, GDF-15, and hsTnT are strongly associated with CV outcomes in HF.
METHODS - This post-hoc analysis used data from a study in which 151 patients with chronic HF due to left ventricular systolic dysfunction were followed up over 10 months. At each visit, N-terminal pro-B-type natriuretic peptide (NT-proBNP), sST2, GDF-15, and hsTnT were measured and any major CV events were recorded.
RESULTS - Baseline values of all 3 novel biomarkers independently predicted total CV events even after adjusting for clinical and biochemical characteristics, including NT-proBNP, with the best model including all 3 biomarkers (p < 0.001). Adding serial measurement to the base model appeared to improve the model's predictive ability (with sST2 showing the most promise), but it is not clear whether this addition is a unique contribution. However, when time-dependent factors were included, only sST2 serial measurement independently added to the risk model (odds ratio: 3.64; 95% confidence interval: 1.37 to 9.67; p = 0.009) and predicted reverse myocardial remodeling (odds ratio: 1.22; 95% confidence interval: 1.04 to 1.43; p = 0.01).
CONCLUSIONS - In patients with chronic HF, baseline measurement of novel biomarkers added independent prognostic information to clinical variables and NT-proBNP. Only serial measurement of sST2 appeared to add prognostic information to baseline concentrations and predicted change in left ventricular function. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting (PROTECT)]; NCT00351390).
Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Relation between soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I and incident atrial fibrillation.
Rienstra M, Yin X, Larson MG, Fontes JD, Magnani JW, McManus DD, McCabe EL, Coglianese EE, Amponsah M, Ho JE, Januzzi JL, Wollert KC, Fradley MG, Vasan RS, Ellinor PT, Wang TJ, Benjamin EJ
(2014) Am Heart J 167: 109-115.e2
MeSH Terms: Aged, Atrial Fibrillation, Biomarkers, C-Reactive Protein, Female, Growth Differentiation Factor 15, Humans, Interleukin-1 Receptor-Like 1 Protein, Male, Middle Aged, Natriuretic Peptide, Brain, Proportional Hazards Models, Receptors, Cell Surface, Risk Assessment, Risk Factors
Show Abstract · Added April 15, 2014
BACKGROUND - We investigated whether circulating concentrations of soluble ST2, growth differentiation factor-15 (GDF-15), and high-sensitivity troponin I (hsTnI) are associated with incident atrial fibrillation (AF) and whether these biomarkers improve current risk prediction models including AF risk factors, B-type natriuretic peptide (BNP), and C-reactive protein (CRP).
METHODS - We studied the relation between soluble ST2, GDF-15, and hsTnI and development of AF in Framingham Heart Study participants without prevalent AF. We used Cox proportional hazard regression analysis to examine the relation of incident AF during a 10-year follow-up period with each biomarker. We adjusted for standard AF clinical risk factors, BNP, and CRP.
RESULTS - The mean age of the 3,217 participants was 59 ± 10 years, and 54% were women. During a 10-year follow-up, 242 participants developed AF. In age- and sex-adjusted models, GDF-15 and hsTnI were associated with risk of incident AF; however, after including the AF risk factors and BNP and CRP, only hsTnI was significantly associated with AF (hazard ratio per 1 SD of loge hsTnI, 1.12, 95% CI 1.00-1.26, P = .045). The c statistic of the base model including AF risk factors, BNP, and CRP was 0.803 (95% CI 0.777-0.830) and did not improve by adding individual or all 3 biomarkers. None of the discrimination and reclassification statistics were significant compared with the base model.
CONCLUSION - In a community-based cohort, circulating hsTnI concentrations were associated with incident AF. None of the novel biomarkers evaluated improved AF risk discrimination or reclassification beyond standard clinical AF risk factors and biomarkers.
© 2014.
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15 MeSH Terms
Association of novel biomarkers of cardiovascular stress with left ventricular hypertrophy and dysfunction: implications for screening.
Xanthakis V, Larson MG, Wollert KC, Aragam J, Cheng S, Ho J, Coglianese E, Levy D, Colucci WS, Michael Felker G, Benjamin EJ, Januzzi JL, Wang TJ, Vasan RS
(2013) J Am Heart Assoc 2: e000399
MeSH Terms: Aged, Biomarkers, Echocardiography, Doppler, Female, Growth Differentiation Factor 15, Humans, Hypertrophy, Left Ventricular, Interleukin-1 Receptor-Like 1 Protein, Logistic Models, Male, Massachusetts, Middle Aged, Multivariate Analysis, Natriuretic Peptide, Brain, Odds Ratio, Predictive Value of Tests, Prevalence, Prognosis, Receptors, Cell Surface, Risk Factors, Stress, Physiological, Stroke Volume, Troponin I, Ventricular Dysfunction, Left, Ventricular Function, Left
Show Abstract · Added April 15, 2014
BACKGROUND - Currently available screening tools for left ventricular (LV) hypertrophy (LVH) and systolic dysfunction (LVSD) are either expensive (echocardiography) or perform suboptimally (B-type natriuretic peptide [BNP]). It is unknown whether newer biomarkers are associated with LVH and LVSD and can serve as screening tools.
METHODS AND RESULTS - We studied 2460 Framingham Study participants (mean age 58 years, 57% women) with measurements of biomarkers mirroring cardiac biomechanical stress (soluble ST-2 [ST2], growth differentiation factor-15 [GDF-15] and high-sensitivity troponin I [hsTnI]) and BNP. We defined LVH as LV mass/height(2) ≥the sex-specific 80th percentile and LVSD as mild/greater impairment of LV ejection fraction (LVEF) or a fractional shortening <0.29. Adjusting for standard risk factors in logistic models, BNP, GDF-15, and hsTnI were associated with the composite echocardiographic outcome (LVH or LVSD), odds ratios (OR) per SD increment in log-biomarker 1.29, 1.14, and 1.18 (95% CI: 1.15 to 1.44, 1.004 to 1.28, and 1.06 to 1.31), respectively. The C-statistic for the composite outcome increased from 0.765 with risk factors to 0.770 adding BNP, to 0.774 adding novel biomarkers. The continuous Net Reclassification Improvement was 0.212 (95% CI: 0.119 to 0.305, P<0.0001) after adding the novel biomarkers to risk factors plus BNP. BNP was associated with LVH and LVSD in multivariable models, whereas GDF-15 was associated with LVSD (OR 1.41, 95% CI: 1.16 to 1.70), and hsTnI with LVH (OR 1.22, 95% CI: 1.09 to 1.36). ST2 was not significantly associated with any outcome.
CONCLUSIONS - Our community-based investigation suggests that cardiac stress biomarkers are associated with LVH and LVSD but may have limited clinical utility as screening tools.
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25 MeSH Terms
Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling.
Ho JE, Chen WY, Chen MH, Larson MG, McCabe EL, Cheng S, Ghorbani A, Coglianese E, Emilsson V, Johnson AD, Walter S, Franceschini N, O'Donnell CJ, CARDIoGRAM Consortium, CHARGE Inflammation Working Group, Dehghan A, Lu C, Levy D, Newton-Cheh C, CHARGE Heart Failure Working Group, Lin H, Felix JF, Schreiter ER, Vasan RS, Januzzi JL, Lee RT, Wang TJ
(2013) J Clin Invest 123: 4208-18
MeSH Terms: Amino Acid Substitution, Female, Gene Expression, Gene Expression Regulation, Genetic Association Studies, HEK293 Cells, Humans, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, Interleukins, Male, Middle Aged, Models, Molecular, Myelin and Lymphocyte-Associated Proteolipid Proteins, Myeloid Differentiation Factor 88, NF-kappa B, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Prospective Studies, Protein Structure, Tertiary, Receptors, Cell Surface, Signal Transduction, Transcription Factor AP-1
Show Abstract · Added April 15, 2014
The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
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23 MeSH Terms
Biomarkers of cardiovascular stress and incident chronic kidney disease.
Ho JE, Hwang SJ, Wollert KC, Larson MG, Cheng S, Kempf T, Vasan RS, Januzzi JL, Wang TJ, Fox CS
(2013) Clin Chem 59: 1613-20
MeSH Terms: Albuminuria, Biomarkers, Cardiovascular Diseases, Female, Growth Differentiation Factor 15, Humans, Incidence, Interleukin-1 Receptor-Like 1 Protein, Kidney Function Tests, Longitudinal Studies, Male, Middle Aged, Receptors, Cell Surface, Renal Insufficiency, Chronic, Troponin I
Show Abstract · Added April 15, 2014
BACKGROUND - Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) are emerging predictors of adverse clinical outcomes. We examined whether circulating concentrations are related to the development of kidney disease in the community.
METHODS - Plasma GDF-15, sST2, and hsTnI concentrations were measured in 2614 Framingham Offspring cohort participants (mean age 57 years, 54% women) at the sixth examination cycle (1995-1998). Associations of biomarkers with incident chronic kidney disease [CKD, eGFR <60 mL · min(-1) · (1.73 m(2)) (-1), n = 276], microalbuminuria (urinary albumin to creatinine ratio ≥25 mg/g in women and 17 mg/g in men, n = 191), and rapid decline in renal function [decline in eGFR ≥3 mL · min(-1) · (1.73 m(2)) (-1) per year, n = 237], were evaluated using multivariable logistic regression; P < 0.006 was considered statistically significant in primary analyses.
RESULTS - Participants were followed over a mean of 9.5 years. Higher plasma GDF-15 was associated with incident CKD [multivariable-adjusted odds ratio (OR) 1.9 per 1-U increase in log-GDF-15, 95% CI 1.6-2.3, P < 0.0001] and rapid decline in renal function (OR, 1.6; 95% CI, 1.3-1.8; P < 0.0001). GDF-15, sST2, and hsTnI had suggestive associations with incident microalbuminuria but did not meet the prespecified P-value threshold after multivariable adjustment. Adding plasma GDF-15 to clinical covariates improved risk prediction of incident CKD: the c-statistic increased from 0.826 to 0.845 (P = 0.0007), and categorical net reclassification was 6.3% (95% CI, 2.7-9.9%).
CONCLUSIONS - Higher circulating GDF-15 is associated with incident renal outcomes and improves risk prediction of incident CKD. These findings may provide insights into the mechanisms of renal injury.
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15 MeSH Terms
Soluble ST2 predicts elevated SBP in the community.
Ho JE, Larson MG, Ghorbani A, Cheng S, Vasan RS, Wang TJ, Januzzi JL
(2013) J Hypertens 31: 1431-6; discussion 1436
MeSH Terms: Aged, Biomarkers, Female, Humans, Hypertension, Interleukin-1 Receptor-Like 1 Protein, Male, Middle Aged, Receptors, Cell Surface, Systole
Show Abstract · Added April 15, 2014
BACKGROUND - Soluble ST2 (sST2) is an emerging prognostic biomarker in patients with existing cardiovascular disease. ST2 and its ligand, interleukin-33 (IL-33), are expressed in endothelial cells, and may play an important role in the development of early atherosclerosis and vascular biology. We sought to investigate the association of sST2 and progression of blood pressure (BP), as well as the development of hypertension.
METHODS - Circulating sST2 concentrations were measured in 1834 participants (mean age 56 years, 57% women) of the community-based Framingham Offspring study. Participants were free of hypertension at baseline. Multivariable linear and logistic regression models were used to evaluate the association of sST2 concentrations and subsequent BP outcomes.
RESULTS - Higher sST2 concentrations were associated with incident hypertension over 3 years of follow-up [multivariable-adjusted odds ratio per 1 standard deviation increase in sST2 1.22, 95% confidence interval 1.05-1.42, P=0.01]. Individuals in the upper sST2 quartile had a 2.6 mmHg greater increase in SBP compared with those in the lowest quartile (P for trend across quartiles 0.002) and a 1.8 mmHg greater increase in pulse pressure (P for trend 0.005). In contrast, sST2 concentrations were not associated with changes in DBP (P=0.27).
CONCLUSION - These findings suggest that sST2 concentrations predict changes in BP physiology typically seen with aging and progressive arterial stiffness. Further studies are needed to elucidate underlying mechanisms by which the ST2/IL-33 pathway may contribute to BP physiology.
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10 MeSH Terms