Serum GDF15 Levels Research Articles

Associations between serum mitokine levels and outcomes in stable COPD: an observational prospective study

Mitokines (Humanin (HN), GDF15 and FGF21) are produced as a result of mitochondrial dysfunction and may have major roles in chronic inflammation, malnutrition and exercise capacity in people with COPD. Except for GDF15, studies on this subject are lacking. A total of 165 patients with stable COPD and 49 smokers without COPD were enrolled. We assessed their serum mitokine levels and clinical characteristics at baseline. We recorded moderate and severe exacerbation for the next 12 months. Baseline serum HN (p = 0.037) and GDF-15 (p = 0.013) levels were higher in the COPD group. High HN levels were independently associated with a high risk of exacerbation (HRE) (OR 2.798, 95% CI 1.266–6.187, p = 0.011), malnutrition (OR 6.645, 95% CI 1.859–23.749, p = 0.004), and 6MWD (OR 0.995, 95% CI 0.991–0.999, p = 0.008), and future moderate (HR 1.826, 95% CI 1.181–2.822, p = 0.007) and severe exacerbations (HR 3.445, 95% CI 1.357–8.740, p = 0.009). High GDF15 levels were associated with HRE (OR 3.028, 95% CI 1.134–8.083, p = 0.027), 6MWD (OR 0.995, 95% CI 0.990–0.999, p = 0.017) and predicted desaturation in 6MWT (OR 3.999, 95% CI 1.487–10.757, p = 0.006). High FGF21 levels were associated with HRE (OR 2.144, 95% CI 1.000–4.600, p = 0.05), and predicted future severe exacerbation (HR 4.217, 95% CI 1.459–12.193, p = 0.008). The mitokine levels were higher in patients with COPD than smokers without COPD, and were associated with important clinical outcomes such as exercise capacity and COPD exacerbation. Among the mitokines, HN showed the strongest association with COPD and may serve as a future risk biomarker in this disease.Trial registation NCT04449419.

Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis

Background and objectivesSystemic sclerosis (SSc) is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement. There are some cytokines with high serum levels of patients with SSc. Our goal is to determine the role of CXCL4, CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers. Patients and methodsObservational case–control study of SSc patients (ACR/EULAR 2013 criteria). Demographic, clinical, analytical, activity, severity, health perception, and disability variables were collected. Moreover, Videocapillaroscopy, Echocardiography and Respiratory Function Test were made. Serum levels of CXCL4, CXCL8 and GDF15 were measured both in SSc patients and in healthy controls. ResultsA total of 42 patients were included (95.4% women), with an average age of 59.2 years and a median of 4 years from diagnosis. We also included 42 healthy controls. We found significantly higher levels of GDF15 in SSc patients than in controls (p<0.001), but no higher CXCL4 or CXCL8 levels. GDF15 was associated with Diffuse SSc, pulmonary arterial hypertension, interstitial lung disease, less forced vital capacity, high titles of antiScl70, disease activity, and dilated loops in capillaroscopy. CXCL4 levels were associated to a higher Rodnan punctuation, while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy. ConclusionsGDF15 high levels were associated with diffuse SSc, lung impairment, disease activity and changes in capillaroscopy. Moreover, CXCL4 was only associated with skin impairment, while CXCL8 was not related to organic damage.

Association between serum GDF-15, myostatin, and sarcopenia in cardiovascular surgery patients.

BackgroundMyostatin is a negative regulator of skeletal muscle mass. On the other hand, growth differentiation factor (GDF)-15 is associated with lower muscle strength and muscle mass. We investigated the relationship between serum GDF-15, myostatin, and sarcopenia in patients receiving cardiovascular surgery through a ROC curve and a multivariate regression analysis.MethodsSkeletal muscle mass index (SMI) by bioelectrical impedance analysis, hand-grip strength, knee extension strength, and walking speed were measured. Preoperative serum GDF-15 and myostatin levels were determined by ELISA. The sarcopenia index could be expressed as: −0.0042 × [myostatin] + 0.0007 × [GDF-15] + 0.0890 × age + 1.4030 × sex − 0.2679 × body mass index (BMI) − 2.1186. A ROC curve was plotted to identify the optimal cutoff level of the sarcopenia index to detect sarcopenia.Results120 patients receiving cardiovascular surgery were included in the study. SMI, hand-grip strength, knee extension strength, and walking speed inversely correlated with GDF-15, but positively correlated with myostatin. In the multivariate stepwise regression analysis, SMI was a determinant of myostatin, and both GDF-15 and myostatin were determinants of SMI and muscle thickness, even after adjustment for age, sex, and BMI. A ROC curve showed that the sarcopenia index was a determinant of sarcopenia (cutoff value −1.0634, area under the curve 0.901, sensitivity 96.9%, specificity 70.9%).ConclusionGDF-15 and myostatin are associated with skeletal muscle volume in patients receiving cardiovascular surgery, but these associations are different. The sarcopenia index calculated from GDF-15 and myostatin levels may be a biomarker of sarcopenia.

Relationship between serum growth differentiation factor 15, fibroblast growth factor-23 and risk of atrial fibrillation: A systematic review and meta-analysis

Background and objectiveGrowth differentiation factor-15 (GDF-15) and fibroblast growth factor-23 (FGF-23) are considered predictors of the incidence of cardiovascular diseases. The present meta-analysis aimed to elucidate the associations between GDF-15 and FGF-23 in the risk of atrial fibrillation (AF).MethodsAn electronic search was conducted in the Cochrane Library, PubMed, and Embase databases from inception until February 27, 2021. The study protocol was registered in the PROSPERO database (CRD42020182226).ResultsIn total, 15 studies that enrolled 36,017 participants were included. Both serum FGF-23 and GDF-15 were elevated in patients with AF. Analysis of categorical variables showed higher serum FGF-23 levels were associated with an increased risk of AF [relative risk (RR) = 1.28, 95% confidence interval (CI): 1.05–1.56]. In contrast, this association was not found with GDF-15 (RR = 0.91, 95% CI: 0.20–4.04). In dose-response analysis, a linear positive association was noted between serum FGF-23 levels and the risk of AF (P nonlinear = 0.9507), with a RR elevation of 7% for every 20 pg/ml increase in the serum FGF-23 levels (95% CI: 1.02–1.13). No remarkable relationship was found between serum GDF-15 levels and the risk of AF, and the overall RR for the association between a 100 ng/L increment in GDF-15 levels and AF was 1.01 (95% CI: 0.998–1.02).ConclusionOur study showed a positive linear correlation between serum FGF-23 levels and the risk of AF. However, no significant association was found between GDF-15 and the risk of AF. Further studies are warranted to clarify whether serum FGF-23 levels may be considered in predicting the risk of AF.Systematic Review Registration: http:www.york.ac.uk/inst/crd, identifier CRD42020182226.

Circulating growth differentiation factor 15 levels and apolipoprotein B to apolipoprotein A1 ratio in coronary artery disease patients with type 2 diabetes mellitus

BackgroundClinical investigations have found that there was a close association between T2DM and adverse cardiovascular events, with possible mechanisms included inflammation, apoptosis, and lipid metabolism disorders. High serum GDF-15 concentration and the apolipoprotein B/apolipoprotein A1 ratio (ApoB/ApoA1) are involved in the above-mentioned mechanisms and are thought to be related to the occurrence of adverse cardiovascular events. However, it remains unclear whether circulating GDF-15 levels and the ApoB/ApoA1 ratio are related to T2DM patients with CAD.MethodsT2DM patients with or without CAD were eligible for this study. According to the inclusion and exclusion criteria, 502 T2DM patients were enrolled between January 2021 and December 2021 and were then divided into T2DM group (n = 249) and CAD group (n = 253). The ApoB, ApoA1 and GDF-15 concentrations were measured at hospital admission and the ApoB/ApoA1 ratio was then calculated.ResultsCompared with T2DM group, serum GDF-15 levels and ApoB/ApoA1 ratio increased in CAD group. Furthermore, a positive relationship between the occurrence of CAD in diabetic population and circulating GDF-15 concentrations and ApoB/ApoA1 ratio was observed in logistic regression analysis (p < 0.01). Restrictive cubic spline analysis after adjusted for multiple risky variables showed that serum GDF-15 or ApoB/ApoA1 ratio correlated positively with CAD.ConclusionsCirculating GDF-15 levels and serum ApoB/ApoA1 ratio vary in CAD group and T2DM group. ApoB/ApoA1 and GDF-15 may be helpful for predicting the occurrence of CAD in patients with T2DM.

Growth Differentiation Factor-15 as a Biomarker for Sarcopenia in Patients With Chronic Obstructive Pulmonary Disease.

PurposeSarcopenia is an important factor contributing to comorbidities in patients with chronic obstructive pulmonary disease (COPD) and is an independent risk factor for increased mortality. The diagnostic process for sarcopenia requires specific equipment and specialized training and is difficult procedurally. A previous study found that GDF15 levels are associated with skeletal muscle mass and function in patients with COPD. However, whether circulating GDF15 levels can be used for the prediction of sarcopenia in patients with COPD is unknown.MethodsThis study included 235 patients with stable COPD who were divided into a development set (n = 117) and a validation set (n = 118), and we followed the definition of sarcopenia as defined by the guidelines from the Asian Working Group for Sarcopenia. Serum concentrations of GDF15 were measured using an enzyme-linked immunosorbent assay (ELISA), and construction of a nomogram and decision curve analysis were performed using the R package “rms.”ResultsIn this study, serum GDF15 levels were negatively associated with skeletal muscle mass (r = –0.204, p = 0.031), handgrip strength (r = –0.274, p = 0.004), quadriceps strength (r = –0.269, p = 0.029), and the thickness (r = –0.338, p < 0.001) and area (r = –0.335, p < 0.001) of the rectus femoris muscle in patients with COPD. Furthermore, the serum levels of GDF15 in patients with sarcopenia were significantly higher than those in controls. Importantly, serum levels of GDF15 could effectively predict sarcopenia in patients with COPD based on the development set (AUC = 0.827) and validation set (AUC = 0.801). Finally, a nomogram model based on serum GDF15 levels and clinical features showed good predictive ability (AUC > 0.89) in the development and validation sets.ConclusionSerum GDF15 levels could be used to accurately and easily evaluate sarcopenia in patients with COPD.

Elevated Expression of Growth Differentiation Factor-15 Is Associated With Acute Exacerbation of Idiopathic Pulmonary Fibrosis

BackgroundsGrowth differentiation factor 15 (GDF-15) is a highly divergent member of the TGF-β superfamily and has been implicated in various biological functions. However, the expression of GDF-15 in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is unclear.MethodThe study included 47 AE-IPF patients, 61 stable IPF (S-IPF) subjects, and 31 healthy controls (HCs). Serum GDF-15 levels and their expression in the lung were measured. The correlation between serum GDF-15 and other clinical parameters and the risk factors for AE occurrence and the survival of IPF patients were analyzed.ResultsSerum GDF-15 levels were significantly elevated in AE-IPF patients (1279.22 ± 540.02 pg/ml) as compared with HCs (891.30 ± 479.90 pg/ml) or S-IPF subjects (107.82 ± 14.21 pg/ml) (both p < 0.001). The protein and mRNA expressions of GDF-15 in the lung of AE-IPF patients were significantly increased as compared with S-IPF cases (p = 0.007 and p = 0.026, respectively). The serum GDF-15 level was correlated with the clinical variables of inflammation, metabolism, and disease severity in IPF subjects (all p < 0.05). The GDF-15 serum concentration was significantly higher in decedents than in survivors (p = 0.005). A serum GDF-15 level above 989.3 pg/ml was a risk factor for AE occurrence (p = 0.04), and the level above 1,075.76 pg/ml was an independent predictor for survival in IPF cases (p = 0.007).ConclusionsThe GDF-15 level was significantly elevated in subjects with AE-IPF. GDF-15 could be a promising biomarker for AE occurrence and survival in IPF patients.

Sex-specific modulation of circulating growth differentiation factor-15 in patients with type 2 diabetes and/or obesity.

ObjectiveGrowth differentiation factor-15 (GDF15), a key metabolic regulator, is associated with obesity and diabetes in which sex-specific differences have been reported. Thus, we assessed whether GDF15 could be dependent on sex in diabetes and/or obesity groups.MethodsWe measured serum GDF15 levels by ELISA in eight lean women and men (n = 16), eight women and eight men having obesity (n = 16), eight women and eight men with type 2 diabetes (T2D, n = 16), and seven women and nine men with both diabetes and obesity (n = 16). Estimation of the difference in the means of each group was performed by two-way ANOVA. The interdependence of the different variates was addressed by multivariate analysis. Correlations between GDF15 levels and HOMA-IR, HbA1c, triglycerides, HDL, and LDL were explored by linear regression.ResultsBeing a woman and having obesity alone or in combination with diabetes decreased GDF15 serum levels (β = −0.47, CI = −0.95, 0.00, P = 0.052; β = −0.45, CI = −0.94, 0.05, P= 0.075). Diabetes independently of metformin treatment and obesity were not predictive of low GDF15 levels (β = 0.10, CI = −0.36, 0.57, P = 0.7). Correlation analysis showed that HOMA-IR (r = 0.45, P = 0.008) and triglycerides (r = 0.41, P = 0.017) were positively correlated and HDL (r = −0.48, P = 0.005) was negatively correlated with GDF15 levels in men.Conclusions/interpretationGDF15 level was significantly different between men and women, as well as between the groups. Sex and group interaction revealed that being a woman and having obesity alone or in combination with diabetes decreased GDF15 levels.

Circulating Growth Differentiation Factor 15 Is Associated with Diabetic Neuropathy.

Background: Growth differentiation factor (GDF15) is a superfamily of transforming growth factor-beta which has been suggested to be correlated with various pathological conditions. The current study aimed to investigate the predicted role of circulating GDF15 in diabetic metabolism characteristics and diabetic neuropathy. Methods: 241 diabetic patients and 42 non-diabetic subjects were included to participate in the study. The plasma GDF15 levels were measured using ELISA. Chronic kidney disease and albuminuria were defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline. The nerve conductive study (NCS) was performed with measurement of distal latency, amplitude, nerve conduction velocity (NCV), H-reflex, and F-wave studies. Results: The diabetic group had a significantly higher prevalence of chronic kidney disease and higher plasma GDF15 level. After adjusting for age and BMI, GDF15 was significantly positively correlated with waist circumference (r = 0.332, p = <0.001), hip circumference (r = 0.339, p < 0.001), HbA1c (r = 0.302, p < 0.001), serum creatine (r = 0.146, p = 0.017), urine albumin/creatinine ratio (r = 0.126, p = 0.040), and HOMA-IR (r = 0.166, p = 0.007). As to NCS, GDF15 was significantly correlated with all latency and amplitude of sensory and motor nerves, as well as F-wave and H-reflex latencies. The area under the curve (AUC) in predicting tibial motor nerve neuropathy (MNCV) in all subjects and in the diabetic group for GDF15 was 0.646 (p = 0.001) and 0.610 (p = 0.012), respectively; for HbA1c was 0.639 (p = 0.001) and 0.604 (p = 0.018), respectively. Predicting ulnar sensory nerve neuropathy for GDF15 was 0.639 (p = 0.001) and 0.658 (p = 0.001), respectively; for HbA1c was 0.545 (p = 0.307) and 0.545 (p = 0.335), respectively. Predicting median sensory nerve neuropathy for GDF15 was 0.633 (p = 0.007) and 0.611 (p = 0.032), respectively; for HbA1c was 0.631 (p = 0.008) and 0.607 (p = 0.038), respectively. Predicting CKD for GDF15 was 0.709 (95% CI, 0.648–0.771), p < 0.001) and 0.676 (95% CI, 0.605–0.746), p < 0.001), respectively; for HbA1c was 0.560 (95% CI, 0.493–0.627); p = 0.080) and 0.515 (95% CI, 0.441–0.588); p = 0.697), respectively. Conclusions: We suggest that there is a significant association between the increased serum GDF-15 level and metabolic parameters and diabetic neuropathy. Plasma GDF15 may be an independent predictor of diabetic neuropathy.

The Diagnostic Value of Serum GDF15 and hs-CTnT in Elderly Patients with Acute Myocardial Infarction.

Objective To analyze the diagnostic value of serum growth differentiation factor 15 (GDFl5) and high-sensitivity troponin T (hs-cTnT) in elderly acute myocardial infarction (AMI). Methods A retrospective analysis of 165 patients with acute chest pain admitted to the Department of Cardiology in our hospital from January to December 2020, Among them, 76 AMI patients (AMI group), 89 non-AMI patients (non-AMI group), and 80 healthy people were selected as the control group during the same period. Compare the three groups of serum GDF15, hs-CTnT levels, and left ventricular ejection fraction (LVEF) parallel correlation analysis, and draw the receiver operating curve (ROC) of serum GDF15 and hs-CTnT levels to diagnose AMI. Results The serum GDF15 and hs-CTnT levels of the AMI group were significantly higher than those of the non-AMI group and the control group, and the difference was statistically significant (p < 0.01). The LVEF was significantly lower than the non-AMI group and the control group, whose difference was statistically significant (p < 0.01). Among them, the indicators of the non-AMI group were both higher and lower than the control group, and the difference was statistically significant (p < 0.01). Serum GDF15 and hs-CTnT levels of AMI patients increased with the increase of NYHA grade, among which grade IV group was significantly higher than grade I∼II group and grade III group (P < 0.01), and grade III group was significantly higher than grade I∼II Group (p < 0.01). Pearson correlation analysis showed that GDF15 and hs-CTnT levels of AMI patients were significantly negatively correlated with LVEF (r = −0.584, −0.612, − < 0.01). The ROC curve showed that GDF15 had a high specificity (93.75%) and hs-CTnT has a high sensitivity (90.67%). The area under the curve for diagnosing AMI is > 0.7 (0.895, 0.948). The sensitivity of the combined detection and the specificity are higher than that of individual detection. Conclusion Serum GDF15 and hs-CTnT are highly expressed in elderly patients with AMI. The combined detection of the two can improve the efficiency of AMI diagnosis. GDF15 can be used as a new biomarker for AMI diagnosis and disease monitoring.

Parishin From Gastrodia Elata Ameliorates Aging Phenotype in Mice in a Gut Microbiota-Related Manner

The physiological and pathological processes that accompany aging can seriously affect the quality of life of the elderly population. Therefore, delaying aging and developing antiaging products have become popular areas of inquiry. Gut microbiota plays an important role in age-related phenotypes. The present study aimed to investigate the antiaging effects and underlying mechanism of parishin, a phenolic glucoside isolated from traditional Chinese medicine Gastrodia elata. Samples from adult (12 weeks), low-dose (10 mg/kg/d) or high-dose (20 mg/kg/d) parishin-treated and untreated aged (19 months) mice were collected to determine blood indicators, gut microbiota and metabolome, and cardiopulmonary histopathological features. The results showed that parishin treatment ameliorates aging-induced cardiopulmonary fibrosis and increase in serum p16Ink4a, GDF15, and IL-6 levels. Furthermore, parishin treatment alleviated dysbiosis in gut microbiota, including altered microbial diversity and the aberrant abundance of opportunistic pathogenic bacteria such as Turicibacter and Erysipelatoclostridium. Gene function prediction and gut metabolome analysis results indicated that the parishin treatment-altered gut microbiota played important roles in sugar, lipid, amino acid and nucleic acid metabolism, and improved gut metabolic disorders in aged mice. In conclusion, the present study provides an experimental basis of potential applications of parishin against aging.

Relationship between the serum GDF-15 concentration and muscle function in female patients receiving aortic valve replacement (TAVR, SAVR): Comparison with healthy elderly female subjects.

PurposeSarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects.MethodsForty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay.ResultsThe GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (β = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement.ConclusionsThe preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia.

A clinical and in-silico study of microRNA-21 and growth differentiation factor-15 expression in pre-diabetes, type 2 diabetes and diabetic nephropathy.

Diabetic nephropathy (DN), a microvascular complication associated with long-standing diabetes, is a major cause of the end-stage renal disease (ESRD). Our in-silico analysis indicates several enrichment analyses involved in glucose metabolism to be affected by GDF15 transcription factors. In-silico analysis was used to identify GDF15 and Insulin related protein-protein interaction (PPI) network and a common set of GDF15 regulating transcription factors by various databases. Common targeting miRNA of GDF15 regulating transcription factors were investigated in miRNet and TargetScan. Further, healthy controls (N.=30) and patients with pre-type-2 diabetes mellitus (pre-diabetes) (N.=30), T2DM (N.=30) and DN (N.=30) were included for analysis of routine biochemical tests, serum GDF15 levels by ELISA and to evaluate the Fold change expression (FCE) of circulating hsa-miR-21 by RT-PCR. MicroRNA-21 was found to directly target GDF15 downregulating transcription factors KLF4, TP53, and CEBPB. A significant difference in the levels of serum GDF15 was observed in Pre-diabetes (708.56±76.37), T2DM (1528.87±140.75) and DN patients (10-fold higher; 5507.90±503.88) when compared to healthy controls (567.36±69.99). The FCE of circulating hsa-miR-21 was 6.19 (pre-diabetes), 8.22 (T2DM), 9.19 (DN), folds higher in cases as compared to controls, reflecting an increasing trend and several folds higher levels of hsa-miR-21 in patients. We suggest the potential of serum GDF15 and circulating-hsa-miR-21 to serve as clinically important biomarkers and therapeutic targets for controlling advancement of diabetes to DN.

Diagnostic utility of GDF15 in neurodegenerative diseases: A systematic review and meta-analysis.

IntroductionGDF15 may be a potential biomarker for neurodegenerative diseases. In this analysis, we aimed to quantitative analysis the levels of GDF15 in patients with neurological diseases and in health control, and then to determine its potential diagnostic utility.MethodsTwo researchers separately conducted a systematic search of the relevant studies up to January 2021 in Embase, PubMed, and Web of Science. Effect sizes were estimated to use the standardized mean difference (SMD) with 95% confidence interval (CI). Sensitivity and specificity were calculated by the summary receiver operating characteristics curve (SROC) method. The sensitivity analysis was performed by the “one‐in/one‐out” approach. Considering the considerable heterogeneity among studies, random‐effects model was used for the meta‐analysis investigation.ResultsA total of eight articles were included in this meta‐analysis and systematic review. The pooled results of the random effect model indicated GDF15 levels were significantly higher in patients with neurodegenerative disease than healthy people (SMD = 0.92, 95% CI: 0.44–1.40, Z = 3.75, p < 0.001). Sensitivity and specificity of biomarker of GDF15 were 0.90 (95% CI: 0.75–0.97), 0.77 (95% CI: 0.67–0.65), and AUC = 0.87 (95% CI: 0.84–0.90), respectively.ConclusionsGDF15 levels were higher in patients with neurodegenerative disease than healthy people. And serum levels of GDF15 were a better marker for diagnostic utility of neurodegenerative disease.

Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis

Background and objectivesSystemic sclerosis (SSc) is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement. There are some cytokines with high serum levels of patients with SSc. Our goal is to determine the role of CXCL4, CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers. Patients and methodsObservational case–control study of SSc patients (ACR/EULAR 2013 criteria). Demographic, clinical, analytical, activity, severity, health perception, and disability variables were collected. Moreover, Videocapillaroscopy, Echocardiography and Respiratory Function Test were made. Serum levels of CXCL4, CXCL8 and GDF15 were measured both in SSc patients and in healthy controls. ResultsA total of 42 patients were included (95.4% women), with an average age of 59.2 years and a median of 4 years from diagnosis. We also included 42 healthy controls. We found significantly higher levels of GDF15 in SSc patients than in controls (p<0.001), but no higher CXCL4 or CXCL8 levels. GDF15 was associated with Diffuse SSc, pulmonary arterial hypertension, interstitial lung disease, less forced vital capacity, high titles of antiScl70, disease activity, and dilated loops in capillaroscopy. CXCL4 levels were associated to a higher Rodnan punctuation, while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy. ConclusionsGDF15 high levels were associated with diffuse SSc, lung impairment, disease activity and changes in capillaroscopy. Moreover, CXCL4 was only associated with skin impairment, while CXCL8 was not related to organic damage.

Ultrasonic Elastography of the Rectus Femoris, a Potential Tool to Predict Sarcopenia in Patients With Chronic Obstructive Pulmonary Disease.

Purpose: Skeletal muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis. Abnormal muscle quantity of the lower limbs is a manifestation of skeletal muscle dysfunction in patients with COPD. Shear wave ultrasound elastography (SWE) is a novel and possible tool to evaluate qualitative muscle parameters. This study explores the feasibility of SWE to measure the stiffness of the rectus femoris and evaluates its value in predicting sarcopenia in patients with COPD.Methods: Ultrasound examination of the rectus femoris was performed to determine the mean elasticity index (SWEmean), cross-sectional area (RFcsa), and thickness (RFthick) using grayscale ultrasonography (US) and SWE in 53 patients with COPD and 23 age-matched non-COPD healthy controls. The serum levels of circulating biomarkers (GDF15, resistin, and TNF-α) were measured using ELISA. The definition of sarcopenia followed the guidelines from the Asian Working Group for Sarcopenia. Receiver operating characteristic (ROC) curve analysis of the SWEmean, RFthick, and RFcsa was used to evaluate their predictive ability for sarcopenia.Results: The intraobserver and interobserver repeatability of SWE performance was excellent (all correlation coefficients > 0.95; p < 0.05). The SWEmean of the rectus femoris in patients with COPD (8.98 ± 3.12 kPa) was decreased compared with that in healthy controls (17.00 ± 5.14 kPa) and decreased with advanced global initiative for chronic obstructive lung disease (GOLD) stage. Furthermore, SWEmean was found to be independent of sex, height, and body mass, and a lower SWEmean in patients with COPD was positively associated with reduced pulmonary function, worse physical function, poor exercise tolerance, decreased muscle strength, and worse dyspnea index score. The correlation between physical function [five-repetition sit-to-stand test (5STST)], muscle function, and SWEmean was higher than those of RFthick and RFcsa. In addition, SWEmean was negatively correlated with serum GDF15 levels (r = −0.472, p < 0.001), serum resistin levels (r = −0.291, p = 0.035), and serum TNF-α levels (r = −0.433, p = 0.001). Finally, the predictive power of SWEmean [area under the curve (AUC): 0.863] in the diagnosis of sarcopenia was higher than that of RFthick (AUC: 0.802) and RFcsa (AUC: 0.816).Conclusion: Compared with grayscale US, SWE was not affected by the patient’s height, weight, or BMI and better represented skeletal muscle function and physical function. Furthermore, SWE is a promising potential tool to predict sarcopenia in patients with COPD.

Longitudinal course of GDF15 levels before acute hospitalization and death in the general population

Past research has shown that childhood adversity (CA) affects the health of older adults; however, the biological mechanisms underlying this association are unclear. Though past research has implicated DNA methylation (DNAm), studies utilizing representative data from older adults and reliable DNAm measures are needed to answer key questions about how stable DNAm changes associated with CA are in later life. Methylation risk scores (MRSs) are an emerging tool that can be used as biomarkers of exposure and as a dimension reduction approach for mediation analyses. This study clarifies the association between CA and later life health by generating MRSs for childhood adversity based on an epigenome wide association study conducted in an independent sample and validating that measure in a nationally representative sample of older adults living in the US from the Health and Retirement Study (HRS), including 2016 methylation data from the HRS Innovative Subsample of the Venous Blood Study. For these 4,018 respondents, DNAm was assessed in whole blood using the Illumina Infinium Human Methylation EPIC BeadChip microarray. Results indicate that retrospective report of childhood SES is significantly associated with an MRS for CA after controlling for demographic factors (viz., race and ethnicity, age, gender, smoking status, and BMI), suggesting that DNAm signal from CA persists across the life course into older adulthood. This study helps clarify the biological processes underlying the association between CA and adult health.

Longitudinal course of GDF15 levels before acute hospitalization and death in the general population

Growth differentiation 15 (GDF15) is a potential novel biomarker of biological aging. To separate the effects of chronological age and birth cohort from biological age, longitudinal studies investigating associations of GDF15 levels with adverse health outcomes are needed. We investigated changes in GDF15 levels over 10 years in an age-stratified sample of the general population and their relation to the risk of acute hospitalization and death. Serum levels of GDF15 were measured three times in 5-year intervals in 2176 participants aged 30, 40, 50, or 60 years from the Danish population-based DAN-MONICA cohort. We assessed the association of single and repeated GDF15 measurements with the risk of non-traumatic acute hospitalizations. We tested whether changes in GDF15 levels over 10 years differed according to the frequency of hospitalizations within 2 years, or survival within 20 years, after the last GDF15 measurement. The change in GDF15 levels over time was dependent on age and sex. Higher GDF15 levels and a greater increase in GDF15 levels were associated with an increased risk of acute hospitalization in adjusted Cox regression analyses. Participants with more frequent admissions within 2 years, and those who died within 20 years, after the last GDF15 measurement already had elevated GDF15 levels at baseline and experienced greater increases in GDF15 levels during the study. The change in GDF15 levels was associated with changes in C-reactive protein and biomarkers of kidney, liver, and cardiac function. Monitoring of GDF15 starting in middle-age could be valuable for the prediction of adverse health outcomes.

Chemokine C-C Motif Ligand 7 (CCL7), a Biomarker of Atherosclerosis, Is Associated with the Severity of Alopecia Areata: A Preliminary Study.

Alopecia areata is an autoimmune, inflammatory form of non-scarring hair loss that may affect any hair-bearing area. Recently, an increased risk of cardiovascular disorders has been described in patients with alopecia areata. The aim of the study was to evaluate the serum concentrations of proinflammatory proteins associated with atherosclerosis (chemokine C-C motif ligand 4; CCL4, chemokine C-C motif ligand 7, CCL7; and sortilin, SORT1), and cardiovascular risk (myeloperoxidase, MPO; interleukin 1 receptor-like 1, IL1RL1; and growth differentiation factor 15, GDF15) in patients with alopecia areata without symptoms or prior cardiovascular disease in comparison with healthy controls. Sixty otherwise healthy patients with alopecia areata and twenty control subjects matched for age, gender, and body mass index (BMI) were enrolled in the study. No significant differences in the serum levels of MPO, IL1RL1, CCL4, CCL7, SORT1, and GDF15 were detected between patients with alopecia areata and healthy controls. A positive correlation was found between the serum concentration of CCL7 and the severity of alopecia areata (r = 0.281, p = 0.03), while GDF15 correlated with age at the disease onset (r = 0.509, p < 0.0001). The results of the present study suggest that the severity of alopecia areata may be associated with an increased risk of atherosclerosis.

Serum GDF15 in β-Thalassemia: A Quantitative Marker of Ineffective Erythropoiesis?

Introduction: Ineffective erythropoiesis (IE) is a crucial hallmark of β-Thalassemia (β-Thal) and sets the goal for treatment of both Transfusion-Dependent (TDT) and Non Transfusion-Dependent Thalassemia (NTDT) patients. The Growth Differentiation Factor (GDF) group has a relevant role in the molecular regulation of IE. Specifically, GDF11 contributes to the inhibition of RBC maturation and it is targeted by activin traps, such as luspatercept. However, its role is still debated; i.e., in a mouse model of β-Thal, the absence of GDF11 alone is not sufficient to mitigate IE (Guerra A et al., Blood, 2019). GDF15 increases from early until late phases of erythroid differentiation and negatively regulates erythroid cell development in-vitro, modulating maturation and apoptosis. (Ranjbaran R et a.l, Exp Cell Res, 2020). A few clinical studies found elevated serum GDF15 levels in β-Thal (Tanno T et al., Nat Med, 2007; Huang Y et al., Int J Med Sci, 2019), but data are sparse and a clear correlation with the severity of the pathology is still missing.Methods: We run an observational study at our institution. At routine checks, patients were asked to consent to a specific blood sample for GDF15, whereas hemoglobin (Hb), serum erythropoietin (Epo), ferritin (Ftn), iron, and transferrin saturation (TSat) were measured as part of clinical practice. In a small subset of patients, a consent for serial sampling was added. Serum GDF15 was measured by ELISA (DuoSet DY957, R&D Systems). Demographics were collected from clinical records. Statistical analysis was performed using Statistica 10 (Statsoft).Results: GDF15 levels were measured in 458 individuals: 267 TDT, 77 NTDT, 45 β-Thal trait carriers (BTC), and 69 healthy (H) subjects. Median (IQR) levels of GDF15 were significantly different among diagnoses (P<0.0001), and specifically measured 0.22 (0.16-0.34) in H, 0.48 (0.28-0.96) in BTC, 1.35 (0.40-5.46) in NTDT and 5.95 (3.19-10.52) ng/mL in TDT. (FIG 1A). In TDT patients, a mild but highly consistent negative correlation was observed between Hb and GDF15 levels (R=-0.31, P=0.002). GDF15 levels correlated positively with Epo (R=0.60, P<0.0001), TSat (R=0.32, P=0.0003) and serum iron (R=0.27, P=0.003). In addition, they correlated with length of transfusion interval in splenectomized patients (R=0.65, P<0.001). In a small subset of longitudinal data in TDT, the transfusion cycle had a strong and uniform effect on GDF15 levels. FIG 1B shows a single individual (female, 38 years old, splenectomized): mean (±SD) GDF15 levels were 5.27 (± 1.99) and 2.10 (±0.97) ng/mL pre-transfusion and 8 days post-transfusion, respectively (P<0.01). After 21 days post-transfusion, they were 3.74 (±0.76), showing a trend of variation opposite to Hb. In another individual with a prenatal diagnosis of severe TDT (homozygous for IVS I:110), GDF15 levels were high at 5 months and showed a progressive decline after the start of regular transfusion therapy. After reaching the 10 mg/dL threshold for pre-transfusion Hb, GDF15 levels were approximately halved compared to 5 months of age (6.2 vs 2.7 ng/mL) (FIG 1C). In NTDT patients, GDF15 correlated positively with TSat (R=0.40, P<0.0001), serum iron (R=0.39, P<0.0001) and Ftn (R=0.25, P=0.01). Among TDT and NTDT patients, 45 and 19 were paediatrics, respectively. No significant differences were observed at different ages. In BTC, GDF15 correlated negatively with Hb levels (R=-0.43, P=0.002) and positively with Epo (R=0.78, P=0.02), TSat (R=0.77, P<0.0001), serum iron (R=0.62, P<0.0001) and Ftn (R=0.59, P<0.0001). No significant correlations were observed for H subjects.Discussion: GDF15 levels correlated with the severity of β-Thal phenotype, showing a 26-fold (TDT), a 6-fold (NTDT) and a 2-fold (BTC) increase compared to controls. In TDT patients, higher GDF15 levels correlated with lower Hb and higher Epo, which are typically observed as a result of IE in thalassemia. In addition, GDF15 correlated with markers of altered iron metabolism, such as TSat and serum iron. In individual patients, GDF15 showed strong and consistent variation with treatment. GDF15 was also associated with quantitative markers of disease in NTDT and BTC patients. This is to our knowledge the larger sample of patients carrying β-thal mutations in which GDF15 levels were measured and correlated with the severity of the disease. These results show that GDF15 may be a suitable and useful quantitative marker of IE. [Display omitted] DisclosuresPiga: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Research Funding. Longo: Bristol Myers Squibb: Honoraria; BlueBird Bio: Honoraria.