Association Of Growth Differentiation Factor 15 Research Articles

A Meta-Analysis of Growth Differentiation Factor-15 and Prognosis in Chronic Heart Failure

Background: Previous studies had reported increased circulating concentrations of growth differentiation factor-15 (GDF-15) in chronic heart failure (CHF), suggesting the potential prognostic significance of GDF-15 in this setting. To verify the relationship between the circulating GDF-15 levels and prognosis of CHF patients, we conducted an updated evidence-based meta-analysis.Methods: A comprehensive literature retrieval of PubMed, EMBASE, and Cochrane library was performed to collect the qualified studies that analyzed the prognostic value of GDF-15 in CHF from the inception of these online databases to September 25, 2021. The hazard ratio (HR) calculated for logGDF-15 of all-cause death and the related 95% confidence interval (CI) in multivariate analysis were used to measure the effect size. Additionally, subgroup analyses stratified by characteristics of the study participants were conducted for incremental evidence of GDF-15 in CHF with different clinical status.Results: A total of ten eligible studies involving 6,244 CHF patients were finally taken into the quantitative analysis. Results in the random-effects model indicated that there was an increased risk of 6% in all-cause mortality with a per 1LnU increase in baseline GDF-15 concentration (HR: 1.06, 95% CI: 1.03–1.10, P < 0.001). In stratified analyses, the association of GDF-15 with risk of all-cause mortality was found among chronic ischemic HF patients (HR:1.75, 95%CI: 1.24–2.48, P = 0.002), while the association was not found among chronic nonischemic HF patients (HR:1.01, 95%CI: 1.00–1.02, P = 0.219).Conclusion: The elevated GDF-15 is associated with an increased risk of all-cause mortality in CHF, especially, among CHF patients with ischemic etiology. The circulating GDF-15 might be a prognostic indicator in CHF patients.Registration Number: https://www.crd.york.ac.uk/PROSPERO; CRD42020210796.

Growth differentiation factor-15 and incident chronic kidney disease: a population-based cohort study

BackgroundThe relationship between growth differentiation factor 15 (GDF-15) and the development of chronic kidney disease (CKD) is still unclear. We sought to examine whether plasma GDF-15 was related to incident CKD and kidney function decline using a large prospective cohort study.Methods4318 participants of the Malmö Diet and Cancer Study-Cardiovascular Cohort were examined in 1991-1994. Incidence of CKD was followed prospectively by linkage with national patient registers. Estimated glomerular filtration rate (eGFR) was available for all participants at baseline, and was re-measured in a subgroup of 2744 subjects after 16.6 ± 1.49 years. Incidence of CKD was examined in relation to GDF-15 using Cox regression analysis. Logistic regression was used to examine the association of GDF-15 with eGFR change and eGFR-based CKD. Models were carefully corrected for potential confounders including baseline eGFR, N-terminal pro-B-type natriuretic peptide, and competing risk from death.Results165 patients developed CKD after 19.2 ± 4.04 years of follow-up. The adjusted hazard ratio (95% confidence interval, CI) for CKD in 4th versus 1st quartile of GDF-15 was 2.37 (1.33, 4.24) (p for trend < 0.01). Each per 1 standard deviation increase in GDF-15 was associated with a decline in eGFR of − 0.97 mL/min/1.73 m2 (95% CI, − 1.49 ~ − 0.45; p < 0.001). GDF-15 was also significantly associated eGFR-based CKD in 2713 subjects with baseline eGFR ≥60 mL/min/1.73 m2.ConclusionsGDF-15 predicted incidence of CKD and eGFR decline in the general population, independent of a wide range of potential risk factors and competing risk of death.

Association of growth differential factor-15, hs-cardiac troponin T and N-terminal pro-brain natriuretic peptide with coronary artery disease in patients undergoing elective coronary angiography

Abstract Background Although the importance of conventional risk factors is well established, a significant proportion of patients with coronary artery disease (CAD) lack any of these factors and many patients without CAD have one or more of them. Better tools are needed to improve risk stratification of patients. Purpose We aimed to investigate the association between plasma levels of growth differentiation factor 15 (GDF-15), a marker of stress and inflammation, high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) with the presence of CAD in stable patients referred for elective coronary angiography. Methods Plasma levels of the three biomarkers were measured in 252 consecutive patients. Patients with known CAD, acute coronary syndrome, or with chronic inflammatory conditions were excluded. CAD was defined by the presence of at least one lesion causing &amp;gt;50% stenosis. The outcome was defined as an ordinal variable with 3 levels: no CAD, 1- or 2-vessel CAD and 3-vessel or left main CAD. Results Median age was 63 years (56–71), and 35% of patients were females. Among conventional risk factors, hypertension was the most prevalent (70%), followed by hyperlipidemia (69%), smoking (42%), diabetes (33%) and family history of CAD (32%). Of the 252 patients enrolled, 153 (61%) had no CAD, 81 (32%) 1- or 2-vessel CAD, and 18 (7%) 3-vessel or left main CAD. Plasma levels of GDF-15, hs-cTnT and NT-proBNP in each of the 3 groups of CAD are summarized in table 1. In unadjusted ordinal logistic regression analysis, GDF-15 and hs-cTnT were statistically significantly associated with the presence and extent of CAD, while NT-proBNP was not (table 1). However, in a multivariable analysis including age, sex and traditional risk factors, the association of GDF-15 and hs-cTnT with angiographic CAD was attenuated and no longer statistically significant. Age, male sex, family history of premature CAD and the presence of hyperlipidemia, were independent predictors of the presence and extent of CAD (table 2). Conclusion In stable patients referred for coronary angiography, plasma levels of GDF-15 and hs-cTnT could predict the presence of CAD when evaluated separately. However, that association was attenuated by clinical characteristics. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Roche Diagnostics International LtdForrenstrasse 26343 RotkreuzSwitzerland Table 1Table 2

Changes in systemic GDF15 across the adult lifespan and their impact on maximal muscle power: the Copenhagen Sarcopenia Study

BackgroundAlthough growth differentiation factor 15 (GDF15) is known to increase with disease and is associated with low physical performance, the role of GDF15 in normal ageing is still not fully understood. Specifically, the influence of circulating GDF15 on impairments in maximal muscle power (a major contributor to functional limitations) and the underlying components has not been investigated.MethodsData from 1305 healthy women and men aged 20 to 93 years from The Copenhagen Sarcopenia Study were analysed. Circulating levels of GDF15 and markers of inflammation (tumor necrosis factor‐alpha, interleukin‐6, and high‐sensitivity C‐reactive protein) were measured by ELISA (R&D Systems) and multiplex bead‐based immunoassays (Bio‐Rad). Relative (normalized to body mass), allometric (normalized to height squared), and specific (normalized to leg muscle mass) muscle power were assessed by the Nottingham power rig [leg extension power (LEP)] and the 30 s sit‐to‐stand (STS) muscle power test. Total body fat, visceral fat, and leg lean mass were assessed by dual energy X‐ray absorptiometry. Leg skeletal muscle index was measured as leg lean mass normalized to body height squared.ResultsSystemic levels of GDF15 increased progressively as a function of age in women (1.1 ± 0.4 pg·mL−1·year−1) and men (3.3 ± 0.6 pg·mL−1·year−1) (both P < 0.05). Notably, GDF15 increased at a faster rate from the age of 65 years in women (11.5 ± 1.2 pg·mL−1·year−1, P < 0.05) and 70 years in men (19.3 ± 2.3 pg·mL−1·year−1, P < 0.05), resulting in higher GDF15 levels in men compared with women above the age of 65 years (P < 0.05). Independently of age and circulatory markers of inflammation, GDF15 was negatively correlated to relative STS power (P < 0.05) but not LEP, in both women and men. These findings were mainly explained by negative associations of GDF15 with specific STS power in women and men (both P < 0.05).ConclusionsA J‐shaped relationship between age and systemic GDF15 was observed, with men at older age showing steeper increases and elevated GDF15 levels compared with women. Importantly, circulating GDF15 was independently and negatively associated with relative STS power, supporting the potential role of GDF15 as a sensitive biomarker of frailty in older people.

Circulating Growth Differentiation Factor 15 Levels Are Associated With Risk of Both Intracerebral and Subarachnoid Hemorrhage.

Background: Growth differentiation factor 15 (GDF-15) has been associated with the risk of developing major bleedings, including but not restricted to intracranial hemorrhages, in patients on oral anticoagulants or dual antiplatelet therapy. We hypothesized that there may be an association of GDF-15 with incidence of hemorrhagic strokes in the general population, which has not been investigated before.Methods: Two different case-control studies, one for intracerebral hemorrhage (ICH) and one for subarachnoid hemorrhage (SAH), nested within the population-based Malmö Diet and Cancer cohort, were defined using the incidence density sampling method. GDF-15 was analyzed in frozen blood samples taken at the baseline examination in 1991–1996. The associations between GDF-15 and incident ICH (220 cases, 244 controls) and incident SAH (79 cases, 261 controls), respectively, were explored using conditional logistic regression adjusting for risk factors.Results: GDF-15 levels at baseline were higher in both incident ICH and SAH cases, compared with their respective control subjects. After adjustment for risk factors, significant relationships with high GDF-15 concentrations were observed both for incident ICH (odds ratio (OR) per 1 log2 unit: 2.27, 95% confidence interval (CI): 1.52–3.41; P = 7.1 × 10−5) and incident SAH (OR: 2.16, 95% CI: 1.29–3.59; P = 0.0032).Conclusions: High circulating GDF-15 levels were associated with incident ICH and incident SAH, independently of the main risk factors.

Growth Differentiation Factor 15 Predicts Cancer Death in Patients With Cardiovascular Risk Factors: The J-HOP Study.

Background: Disease-related anorexia-cachexia is associated with poor prognosis of patients with cardiovascular disease (CVD) or cancer. Growth differentiation factor-15 (GDF-15) has emerged as a central regulator of appetite and body weight. However, the exact role of GDF-15 in lean patients has not been elucidated.Aim: Our aim is to evaluate whether the association of GDF-15 with mortality, including cancer death, differs according to body mass index (BMI) level.Methods and Results: We collected blood samples from 4,061 patients with CV risk factors who were enrolled in the nationwide practice-based J-HOP (Japan Morning Surge-Home Blood Pressure) study. Serum GDF-15 levels were determined by immunoassay analysis. During a mean follow-up period of 6.6 years, we observed 174 (6.7/1000 person-year) all-cause deaths, 68 (2.6/1000 person-year) cancer deaths, and 56 (2.2/1000 person-year) CV deaths. Patients were stratified according to the cut-points of GDF-15 at 1,200 ng/L and BMI at 22.5 and 25.0 kg/m2. The association between the GDF-15/BMI based study groups and each outcome was evaluated by Cox-proportional hazard models with adjustment for established risk factors. The multivariate Cox regression model showed that patients with elevated GDF-15 (≥1,200 ng/L) and low BMI (<22.5 kg/m2) were significantly associated with increased risk of all outcomes [all-cause death, hazard ratio (HR) 3.15, 95% confidence interval (CI) 1.85–5.34, p < 0.001; cancer death, HR 3.52, 95%CI 1.64–7.57, p = 0.001; CV death, HR 2.88, 95%CI 1.20–6.92, p = 0.018, respectively] compared to a reference group with non-elevated GDF-15 and normal BMI (22.5–25.0 kg/m2). In analyses of a subgroup with low BMI (<22.5 kg/m2), patients with elevated GDF-15 had 4.79-fold increased risk of cancer death and 11-fold greater risk of CV death when compared with patients with non-elevated GDF-15 (<1,200 ng/L) after adjustment for established risk factors.Conclusion: In patients with CV risk factors, GDF-15 was associated with all-cause, cancer, and CV death. This relationship was especially remarkable in patients with low BMI. The serum GDF-15 levels in patients with low BMI might be a useful marker to identify the potential for anorexia-cachexia associated with CVD and cancer.

Abstract P009: Growth Differentiation Factor 15 And The Subsequent Risk Of Atrial Fibrillation: The Atherosclerosis Risk In Communities Study

Introduction: Growth differentiation factor 15 (GDF-15) is a marker of oxidative stress and inflammation and has been associated with several cardiovascular disease (CVD) phenotypes. However, conflicting results have been reported regarding the association of GDF-15 with incident atrial fibrillation (AF) in the general population. Hypotheses: Higher GDF-15 level is associated with increased risk of incident AF independent of potential confounders. Methods: In 10,101 White and Black ARIC participants (mean age 60 years and 20.9% Blacks) free of AF at baseline (1993-95), we quantified the association of GDF-15 and incident AF using three Cox proportional hazards models. GDF-15 was measured by SOMA scan assay. AF was defined by hospitalizations with AF diagnosis or death certificates (ICD-9 codes: 427.31-427.32; ICD-10 codes: I48.x) or AF diagnosis by ECG at subsequent ARIC visits. Results: There were 2165 cases of incident AF over a median follow-up of 20.7 years (incidence rate 12.1 cases/1,000 person-years). After adjusting for demographic characteristics and cardiovascular risk factors, log GDF-15 was significantly associated with incident AF (hazard ratio 1.42 (1.25-1.63) for top vs. bottom quartile) (Model 1 in Table ). The result was robust even further adjusting for history of other CVD phenotypes and cardiac markers (Models 2 and 3 in Table ). In Model 3, quartiles of high-sensitive cardiac troponin T (hs-cTnT) did not demonstrate significant associations with incident AF. Conclusions: In community-based population, elevated GDF-15 level was independently and robustly associated with incident AF (even more strongly than troponin). These results suggest the involvement of GDF-15 in the development of AF and the potential of GDF-15 as a risk marker to identify individuals at high risk of AF.

Growth differentiation factor 15 (GDF-15) as potential cardiovascular risk biomarker in antiphospholipid syndrome.

An interplay between thrombo-inflammatory and atherogenic mechanisms is recognized in cardiovascular disease (CVD) pathogenesis in APS. Herein, we examine associations of growth differentiation factor-15 (GDF-15), a pro-inflammatory cytokine identified as a potent CVD risk biomarker in the general population, with subclinical atherosclerosis in APS. We measured plasma GDF-15 levels by an electrochemiluminescence immunoassay (cut-off 1200 pg/ml) and we examined carotid intima-media thickness (IMT) and the presence of carotid and femoral plaques using vascular ultrasound in 80 patients with APS (44 primary, 36 SLE/APS) and 40 healthy controls. We calculated the adjusted Global APS Score for cardiovascular disease (aGAPSSCVD), a revised adjusted Global APS Score (aGAPSS) for predicting CVD, including lupus anticoagulant, anticardiolipin and anti-beta2glycoprotein-I antibodies, and hypertension, dyslipidaemia, obesity, diabetes and smoking. GDF-15 levels were higher in APS patients vs controls, after adjusting for age and gender [absolute difference: 281 (95% CI: 141, 421) pg/ml, P < 0.001]. GDF-15 levels ≥1200 pg/ml were associated with higher mean IMT of the right and left carotid arteries [beta coefficient 0.068 (95% CI: 0.020, 0.116), P = 0.006] compared with GDF-15 levels <1200 pg/ml. GDF-15 was independently associated with mean IMT, after adjusting for gender and aGAPSSCVD [beta coefficient 0.059 (95% CI: 0.008, 0.110), P = 0.024], and additionally for statin (P = 0.025) and HCQ use (P = 0.011). GDF-15 levels ≥1200 pg/ml were associated with 2.4 times higher odds for atherosclerotic plaques (odds ratios = 2.438, 95% CI: 0.906, 6.556, P = 0.078), while this effect was reduced by including more covariates in the model. GDF-15 is independently associated with subclinical atherosclerosis in APS patients, suggesting its potential role in CVD risk stratification in APS.

Associations of GDF-15 and GDF-15/adiponectin ratio with odds of type 2 diabetes in the Chinese population.

We elucidate the effect of Growth differentiation factor-15(GDF-15)/adiponectin ratio in improving the assessment value for odds of type 2 diabetes. Cross-sectional design. A total of 405 participants (135 patients with newly diagnosed type 2 diabetes, 135 age- and sex-matched participants with prediabetes, and 135 healthy controls) were collected from Guangzhou and Dongguan, China. The serum GDF-15 and adiponectin levels were measured by ELISA and latex-enhanced immunoturbidimetry. Logistic regression analysis and restricted cubic splines were used to evaluate the associations between diabetes and the indicators. The low level of adiponectin and high GDF-15/adiponectin ratio were significantly associated with increased odds of type 2 diabetes, but not for GDF-15. Three clusters were identified based on the K-means clustering analysis. Compared to the lowest quartiles of adiponectin, the OR and 95% CI of the highest adiponectin with type 2 diabetes was 0.24 (0.07-0.74, p trend = 0.004) after adjusting for sex, age, BMI, and DBP only in cluster 1. After adjusting for confounding factors, subjects with the highest GDF-15/adiponectin ratio quartiles had 3.9 times (OR = 3.85, 95% CI = 0.76-24.25) and 3.8 times (OR = 3.80, 95% CI = 1.02-14.68) higher odds of type 2 diabetes in cluster 2 and cluster 3, respectively. The association between the GDF-15/adiponectin ratio and type 2 diabetes was attenuated, but still remarkable (OR = 3.18, 95% CI = 1.11-10.18), in cluster 1. Higher GDF-15/adiponectin ratio is independently associated with increased odds of type 2 diabetes for all study populations, suggesting that the GDF-15/adiponectin ratio may be a better indicator of type 2 diabetes.

Growth Differentiation Factor (GDF)-15 and Cardiometabolic Outcomes among Older Adults: The Atherosclerosis Risk in Communities Study.

Laboratory studies suggest an involvement of growth differentiation factor 15 (GDF-15) in metabolic dysregulation. However, the utility of GDF-15 for assessing risk of cardiometabolic outcomes has not been rigorously examined among older adults. We conducted a cross-sectional analysis of older adults who attended visit 6 (2016-2017) of the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to quantify cross-sectional associations of GDF-15 (in quartiles) with prevalent diabetes, obesity, atherosclerotic cardiovascular disease (ASCVD), subclinical myocardial stress/injury (assessed by NT-proB-type Natriuretic Peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT]), and heart failure (HF). Among 3792 ARIC study participants (mean age 80 years, 59% women, 23% Blacks and 77% Whites, mean GDF-15: 2094.9 pg/mL [SD: 1395.6]), higher GDF-15 concentrations (highest vs. lowest quartile) were positively associated with diabetes (adjusted odds ratio [aOR]:] : 2.48, 95% CI : 1.89, 3.26), ASCVD (aOR: 1.57, 95% CI: 1.16, 2.11), increased hscTnT (aOR: 2.27, 95%CI: 1.54, 3.34), increased NT-proBNP (aOR: 1.98, 95%CI: 1.46, 2.70), and HF (aOR: 3.22, 95%CI : 2.13, 4.85), in models adjusted for demographics and traditional cardiovascular risk factors. In this sample of older US black and whites, increased GDF-15 was positively associated with diabetes, ASCVD, HF, and markers of subclinical myocardial stress or injury. These results illustrate the diverse aspects of the link between GDF-15 and diseases states, and its potential utility as robust biomarker of adverse cardiometabolic outcomes.

GDF15 as a biomarker of ageing.

The ageing process is accompanied by the gradual development of chronic systemic inflammation (inflamm-ageing). Growth differentiation factor 15 (GDF15) is associated with inflammation and known to be a stress-induced factor. The present study aimed to explore the association of GDF15 with ageing. In this cross-sectional study, serum GDF15, hematological parameters, and biomedical parameters were determined in 120 healthy individuals (23-83years old, males). Three telomere related parameters, including telomere length, telomerase activity, and the expression of human telomerase reverse transcriptase (hTERT) mRNA were also quantified. Our results showed that the older group has a higher levels of GDF15 and lower expression of hTERT mRNA, and PBMC telomerase activity (p<0.001). In individuals with high GDF15 levels, they were older, and presented with the lower level of hTERT mRNA and T/S ratio (p<0.01). Spearman correlation analysis shows that GDF15 positively correlated with age (r=0.664, p<0.001), and negatively correlated with telomere length (r=-0.434, p<0.001), telomerase activity (r=-0.231, p=0.012), and hTERT mRNA (r=-0.206, p=0.024). Furthermore, in multivariate regression analysis, GDF15 levels showed a statistically significant linear and negative relationship with PBMC telomerase activity (β-coefficient=-0.583, 95% CI -1.044 to -0.122, p=0.014), telomere length (β-coefficient=-0.200, 95% CI -0.305 to -0.094, p<0.001), and hTERT mRNA (β-coefficient=-0.207, 95% CI -0.312 to -0.102, p<0.001) after adjusting for confounders. These results support that circulating GDF15 is the potential biomarker of ageing that may influence the risk and progression of multiple ageing conditions.

A study of serum growth differentiation factor 15 in Indian women with and without gestational diabetes mellitus in the third trimester of pregnancy and its association with pro-inflammatory markers and glucose metabolism

The pathogenesis of gestational diabetes mellitus (GDM) is multifactorial and it shares many features with type 2 diabetes mellitus. Growth differentiation factor 15 (GDF-15), a member of transforming growth factor-β superfamily, is expressed in a high amount in the placenta in addition to other organs. This cross-sectional study was performed to assess the difference of GDF-15 and pro-inflammatory cytokines between pregnant women with or without GDM, and to explore the possible association of GDF-15 with the parameters of dysglycemia (Serum insulin, HOMA-IR, fasting, 60min, and 120min post-75 gm oral glucose plasma glucose levels) and inflammation (IL-6 and TNF-α) in women with GDM at 24-28weeks of gestation. Thirty-five women with GDM and 30 age-matched non-diabetic pregnant control (NDPC) subjects were recruited for the study. Mean serum GDF-15, IL-6, and TNF-α levels were significantly higher in GDM in comparison to the NDPC population. These differences persisted even after adjusting for the possible confounders like maternal age and BMI. GDF-15 level showed a positive correlation with parameters of dysglycemia (Serum insulin, HOMA-IR, fasting, 60min, and 120min post-75 gm oral glucose plasma glucose levels) but a variable correlation with the markers of inflammation. In conclusion, our study provides evidence that, in Indian women, serum GDF-15 level is higher in GDM in comparison to age-matched pregnant subjects without GDM in the early third trimester pregnancy. Moreover, in third trimester, GDF-15 level increases with increase in plasma glucose and insulin resistance.

Abstract 13846: Growth Differentiation Factor 15 and Risk of Clinical Bleeding Events in the Atherosclerosis in Communities (ARIC) Study

Introduction: Growth differentiation factor 15 (GDF15), a cytokine growth factor, is a predictor of bleeding in people with cardiovascular disease (CVD). Potential mechanisms include direct inhibition of platelet activity or as a marker of tissue vulnerability. Hypothesis: We hypothesized that GDF15 will also be associated with bleeding in individuals without a history of CVD. Methods: We studied the association of GDF15 with clinical bleeding events among 9,850 ARIC participants without prior bleeding and CVD at baseline (mean age 60 years, 57% female, 21% black). Serum levels of GDF15 were measured in relative fluorescence units using DNA-based aptamer technology (SOMA scan assay). Bleeding events were ascertained using discharge codes. We examined incidence rates for bleeding using Poisson models, hazard ratios (HRs) of incident bleeding using Cox models, and the improvement in risk prediction of bleeding using the Harrell’s- c statistic with the addition of GDF15 to established predictors in a commonly used bleeding risk score. Results: There were 1,291 hospitalizations with bleeding during a median follow up of 22.1 years through 2018, with the majority (87.8%) being gastrointestinal bleeding. The incidence rate of bleeding per 1,000 person-years was 3.4 in the highest quartile of GDF15 and 1.8 in the lowest quartile. The highest quartile of GDF15 was associated with an adjusted HR of 1.52 (95% CI 1.27-1.81) for total bleeding and 1.55 (1.28-1.88) for gastrointestinal bleeding compared to the lowest quartile. The addition of GDF15 to a validated bleeding risk score improved the c- statistic by 0.030 (0.010-0.50) from 0.640 to 0.669. Conclusions: Higher levels of GDF15 were robustly associated with bleeding hospitalizations and improved risk prediction beyond conventional bleeding risk factors. Our results suggest the etiological contributions of GDF15 to bleeding and its potential usefulness for risk classification of bleeding in individuals without CVD.

Association of serum growth differentiation factor-15 with eGFR and hemoglobin in healthy older females.

PurposeAnemia and sarcopenia associated with renal dysfunction caused by cytokine imbalance can contribute to decreased quality of life for older individuals. Growth differentiation factor-15 (GDF-15) is associated with renal dysfunction, although whether it is related to anemia or sarcopenia is unclear. In this study we examined the association of GDF-15 with renal function, hemoglobin and sarcopenia in healthy community-dwelling older females in Japan.MethodsA total of 66 healthy older community-dwelling females (age: 75.8 ± 6.2 years) were enrolled for this study. Skeletal muscle mass index was determined by bioelectrical impedance analysis. Hand-grip strength and walking speed were also assessed. Serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay and both hemoglobin (Hb) level and estimated glomerular filtration rate (eGFR) were measured.ResultsSerum GDF-15 levels positively correlated with age but negatively correlated with eGFR and walking speed. In multiple regression analysis, eGFR and hemoglobin (Hb) were independent variables to predict serum GDF-15 levels, even after adjusting for age and body mass index (eGFR: β = −0.423, p < 0.001; Hb: β = −0.363, p = 0.004). Serum GDF-15 level was an independent variable to predict eGFR and Hb.ConclusionsBoth Hb and eGFR are predictors for serum GDF-15 concentration in healthy older females. In these community-dwelling older females, renal dysfunction via GDF-15 may be accompanied by anemia, but not sarcopenia.

Associations Between Serum GDF15 Concentrations, Muscle Mass, and Strength Show Sex-Specific Differences in Older Hospital Patients.

Aging is accompanied by a progressive decline of muscle mass and strength and also higher levels of circulating cytokines such as growth differentiation factor 15 (GDF15). Studies evaluating the association of GDF15 with muscle mass and strength are rare. In this analysis, we investigated GDF15 concentrations and their relationship with muscle mass and strength in older men compared with women. GDF15 serum concentrations were measured in 103 (60 years and older) hospital patients and an age-matched control group with an immunosorbent assay. Skeletal muscle mass was determined with the bioelectrical impedance analysis. Grip strength and knee extension strength were assessed and normalized for height. Associations between GDF15 concentrations and muscle mass and strength were evaluated with general linear models. Male patients showed higher levels of GDF15 compared with female patients (p = 0.021). Elevated GDF15 concentrations were associated with lower measures of muscle mass, exclusively in men, after adjustment for age and number of drugs per day. Our results indicate sex differences between associations of GDF15 with muscle mass and strength parameters in a cohort of older hospital patients.

1273-P: Growth Differentiation Factor 15 (GDF15) Is Associated with Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Youth

Growth differentiation factor 15 (GDF15) has been associated with many important biological functions, such as food intake and weight regulation in response to metabolic stress. In animal models, it has also been noted that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in children. Nevertheless, the exact role of GDF15 in liver disease has yet to be elucidated. We aimed to explore the association of GDF15 with NAFLD in obese youth, and whether GDF15 changes similarly with changes in hepatic fat content (HFF%) over time. Fasting plasma GDF15 levels were measured by ELISA in obese youth with (89) and without (95) NAFLD. Additionally, fasting GDF15 levels were measured in 22 obese youth who progressed (11) or regressed (11) in HFF% by more than 30% over a two-year period. Abdominal MRI was performed on all subjects to quantify HFF%. For the first time, we describe a novel association between GDF15 and NAFLD in obese youth. Figure 1A shows a statistically significant difference in fasting GDF15 levels (p&amp;lt;0.0001) between three groups stratified by degree of HFF%. Figure 1B shows a statistically significant association between change in HFF% and change in GDF15 (p=0.01; r2=0.29). These data suggest that GDF15 levels change with change in intrahepatic fat content in obese youth and may serve as a biomarker for NAFLD in children. Disclosure B. Galuppo: None. C. Agazzi: None. B. Pierpont: None. S. Samuels: None. E. Tarabra: None. S. Caprio: None. N. Santoro: None.

The impact of GDF-15, a biomarker for metformin, on the risk of coronary artery disease, breast and colorectal cancer, and type 2 diabetes and metabolic traits: a Mendelian randomisation study.

Growth differentiation factor 15 (GDF-15), a suggested biomarker for metformin use, may explain the potential cardioprotective and anti-cancer properties of metformin. We conducted a Mendelian randomisation study to examine the role of GDF-15 in risk of coronary artery disease (CAD) and breast and colorectal cancer. Secondary analyses included examination of the association of GDF-15 with type 2 diabetes, glycaemic traits, BP, lipids and BMI. We obtained SNPs strongly (p value <5 × 10-8) predicting GDF-15 from a genome-wide association study (GWAS) (n = 5440) and applied them to genetic studies of CAD (CARDIoGRAMplusC4D 1000 Genomes-based GWAS [n = 184,305]), type 2 diabetes (DIAGRAM [DIAbetes Genetics Replication And Meta-analysis; n = 898,130]), glycaemic traits (MAGIC [the Meta-Analyses of Glucose and Insulin-related traits Consortium; HbA1c: n = 123,665; fasting glucose: n = 46,186]), BP, breast cancer and colorectal cancer (UK Biobank [n ≤ 401,447]), lipids (GLGC [Global Lipids Genetic Consortium; n ≤ 92,820]) and adiposity (GIANT [Genetic Investigation of ANthropometric Traits Consortium; n = 681,275]). Causal estimates were obtained using inverse variance weighting, taking into account correlations between SNPs. Sensitivity analyses included focusing on the lead SNP (rs888663) and validation for CAD in the UK Biobank and for breast cancer in the Breast Cancer Association Consortium. Using 5 SNPs, increased GDF-15 was associated with lower CAD (OR 0.93 per SD increase, 95% CI 0.87, 0.99) and breast cancer (OR 0.89 per SD increase, 95% CI 0.82, 0.96), with similar results from lead SNP analysis. However, the associations with CAD (OR 0.99 per SD increase, 95% CI 0.93, 1.04) and breast cancer (OR 0.97 per SD increase, 95% CI 0.94, 1.01) in the validation studies were not as apparent. GDF-15 was not associated with type 2 diabetes, glycaemic traits, CAD risk factors or colorectal cancer. There is no convincing evidence that GDF-15 reduces risk of CAD or breast or colorectal cancer. Whether the observed inverse association of metformin use with cancer risk is via other unexplored mechanistic pathways warrants further investigation.

Association of circulating growth differentiation factor-15, Krüppel-like factor 4 and growth arrest-specific 6 with coronary artery disease

BackgroundCurrent assessment tools for patients with acute chest pain are either traumatic (coronary angiography) or unreliable (measurement of cardiac troponin concentrations). We investigated whether the novel cardiovascular stress markers, serum growth differentiation factor-15 (GDF-15), Krüppel-like factor 4 (KLF4) and growth arrest-specific 6 (gas6) may be useful biomarkers of coronary artery disease (CAD). MethodsA total of 350 male patients were enrolled, 198 with CAD and 152 controls, based on coronary angiography. GDF-15, KLF4 and gas6 concentrations were measured using commercial enzyme-linked immunosorbent assay kits. Multivariate logistic regression and multivariate linear regression were performed to evaluate potential associations of GDF-15, KLF4 and gas6 with risk of CAD or CAD severity. ResultsSerum GDF-15, KLF4 and gas6 concentrations were significantly higher in male patients with CAD than in control subjects (P < .05), and they correlated significantly with involvement of coronary vessels (P < .05). After adjusting for confounding factors, we found that circulating GDF-15 concentrations remained positively associated with the presence of CAD (odds ratio [OR] per 1-standard deviation [SD] increase, 3.182; 95% confidence interval [CI] 1.586 to 6.382; P = .001), as did KLF4 concentrations (OR per 1-SD increase, 13.05; 95% CI 2.940 to 57.921, P = .001). Moreover, circulating GDF-15 concentrations were positively associated with the Gensini score (estimated SD change per 1-SD increase, 22.091; 95% CI 9.147 to 35.035, P = .001), as were KLF4 concentrations (estimated SD change per 1-SD increase, 27.996; 95% CI 10.082 to 45.910, P = .002). Gas6, in contrast, showed no relationship to presence of CAD or Gensini score., ConclusionsIn this case-control study, increased concentrations of circulating GDF-15 and KLF4 were significantly associated with the presence and severity of CAD.

Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension

IntroductionSkeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other...

Growth differentiation factor-15 is not modified by sacubitril/valsartan and is an independent marker of risk in patients with heart failure and reduced ejection fraction: the PARADIGM-HF trial.

Growth differentiation factor-15 (GDF-15) is associated with adverse prognosis in cardiovascular (CV) and non-CV diseases. We evaluated the association of GDF-15 with CV and non-CV outcomes in the PARADIGM-HF trial. In 1935 patients with heart failure and reduced ejection fraction (HFrEF) in PARADIGM-HF, median GDF-15 values were elevated and similar in sacubitril/valsartan and enalapril patients (1626 ng/L and 1690 ng/L, respectively). Diabetes, age, creatinine, high-sensitive troponin T, N-terminal pro-B-type natriuretic peptide, and New York Heart Association class III/IV were most strongly associated with elevated GDF-15 values (all P < 0.001) (adjusted R2 = 0.3857). Baseline GDF-15 and changes in GDF-15 at both 1 month and 8 months (log-transformed) were associated with subsequent mortality and CV events. Each 20% increment in baseline GDF-15 value was associated with a higher risk of mortality [adjusted hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.08-1.18, P < 0.001], the combined endpoint of CV death or hospitalization for heart failure (adjusted HR 1.09, 95% CI 1.05-1.14, P < 0.001) and heart failure death (adjusted HR 1.16, 95% CI 1.05-1.28, P < 0.001). Changes in GDF-15 were not influenced by assigned therapy (all P-values ≥ 0.1). In patients with ambulatory HFrEF, GDF-15 is not modified by sacubitril/valsartan and is strongly associated with mortality and CV outcomes, suggesting that GDF-15 is a marker of poor outcomes in these patients. ClinicalTrials.gov Identifier NCT01035255.