Association Of Growth Differentiation Factor 15 Research Articles

Convalescent Growth Differentiation Factor-15 and Long-Term Outcomes after an Acute Coronary Syndrome.

Growth differentiation factor-15 (GDF-15) has been shown to be associated with adverse clinical outcomes in patients after an acute coronary syndrome when measured soon after an event. Although dynamic in the acute phase after myocardial injury, GDF-15 has been shown to remain stable during convalescence. In this study, we aimed to assess the value of GDF-15 as a long-term prognostic marker for clinical outcomes when measured in the convalescent phase following an acute coronary syndrome. GDF-15 concentrations were measured in 1945 patients who were recruited between 2002 and 2009 to the Coronary Disease Cohort Study. For this analysis, follow-up was curtailed at 10 years and association of GDF-15 with all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure hospitalizations were assessed with multivariate Cox proportional hazard regression analysis. After 10 years of follow-up, there were 648 deaths (348 from cardiovascular causes), 500 admissions for myocardial infarction, and 436 for heart failure. Four-month convalescent GDF-15 demonstrated a robust independent association with all endpoints, which remained after adjustment for Global Registry of Acute Coronary Events score and other convalescent biomarkers. When compared to the lowest quartile of GDF-15 concentrations, those in the highest quartile had a 3-fold increased risk of all-cause death. Convalescent plasma GDF-15 is a strong and independent predictor of 10-year all-cause death, cardiovascular death, recurrent myocardial infarction, and heart failure admission following an acute coronary syndrome. ACTRN12605000431628.

Growth Differentiation Factor 15 and Diet Quality Trajectory Interact to Determine Frailty Incidence among Middle-Aged Urban Adults

BackgroundElevated plasma growth differentiation factor 15 (GDF15) and poor diet quality may be associated with increased frailty incidence, although their interactive associations have not been assessed in urban middle-aged adults. ObjectivesWe aimed to examine GDF15 and its interactive association with diet quality in relation to frailty incidence among a sample of middle-aged urban adults. MethodsThe relationship between GDF15 and diet quality trajectories in relation to incident frailty was examined in a longitudinal study of participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (2004–2017). Serum GDF15 concentration and frailty incidence were primary exposure and outcome, respectively. Group-based trajectory models were used to assess diet quality trajectories (≤3 visits/participant, N = 945, N′ = 2247 observations) using the Healthy Eating Index 2010 version (HEI-2010), Dietary Inflammatory Index, and mean adequacy ratio (MAR). Cox proportional hazards models were used, testing interactive associations of GDF15 and diet quality trajectories with frail/prefrail incidence (N = 400 frailty-free at first visit, N′ = 604 observations, n = 168 incident frail/prefrail). ResultsBoth elevated GDF15 and lower diet quality trajectories were associated with a lower probability of remaining nonfrail (≤13 y follow-up). Among females, the “high diet quality” HEI-2010 trajectory had a hazard ratio (HR) of 0.15 [95% confidence interval (CI): 0.04, 0.54; P = 0.004; fully adjusted model] when compared with the “low diet quality” trajectory group. Among males only, there was an antagonistic interaction between lower HEI-2010 trajectory and elevated GDF15. Specifically, the HR for GDF15-frailty in the higher diet quality trajectory group (high/medium combined), and among males, was 2.69 (95% CI: 1.06, 6.62; P = 0.032), whereas among the lower diet quality trajectory group, the HR was 0.94 (95% CI: 0.49, 1.80; P = 0.86). Elevated GDF15 was independently associated with frailty among African American adults. ConclusionsPending replication, we found an antagonistic interaction between GDF15 and HEI-2010 trajectory in relation to frailty incidence among males.

Growth differentiation factor-15 as a negative predictor for microvascular obstruction in ST-segment elevation myocardial infarction after primary percutaneous coronary intervention.

Growth differentiation factor-15 (GDF-15) is an anti-inflammatory cytokine with cardioprotective effects, but circulating GDF-15 concentration predicts adverse cardiovascular outcomes in clinical settings. Microvascular obstruction (MVO) formation contributed to poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (pPCI). We aimed to investigate GDF-15 concentration in relation to cardiac magnetic resonance (CMR)-derived MVO in STEMI patients after pPCI, which might help better understand the role of GDF-15 in STEMI. GDF-15 levels at 6h after pPCI and MVO extent at day 5 ± 2 after pPCI were measured in 74 STEMI patients (mean age 60.3 ± 12.8years, 86.5% men). The adjusted association of GDF-15 with MVO was analyzed with MVO treated as a categorized variable (extensive MVO, defined as MVO extent ≥ 2.6% of left ventricular (LV)) and a continuous variable (MVO mass, % of LV), respectively, in multivariate logistic and linear regression models. 41.9% of the patients developed extensive MVO after pPCI. In multivariate analysis, the odds ratio (95% confidential interval (CI)) of each standard deviation (SD) increase in GDF-15 for developing extensive MVO was 0.46 (0.21, 0.82), p = 0.02). Consistently, when MVO was used a continuous variable, each SD increase in GDF-15 was associated with a substantially lower MVO mass (β - 0.42, standard error 0.19, p = 0.03). GDF-15 was a negative predictor for MVO in STEMI patients after pPCI. The observation was consistent with results from experiment studies, suggesting a potential protective effect of GDF-15 against cardiac injury.

Abstract 16679: Growth Differentiation Factor 15 in the Initial Evaluation of Suspected Coronary Artery Disease

Introduction: The cytokine growth differentiation factor 15 (GDF-15) is expressed in several tissues including cardiomyocytes, and is up-regulated in conditions of tissue injury and stress. Hypothesis: We hypothesized that serum GDF-15 can predict obstructive CAD and need of revascularization among acutely admitted chest pain patients. Further, we assessed whether the combination of GDF-15 and coronary artery calcium (CAC) scoring could identify a subgroup with low risk of obstructive CAD, in whom a full coronary CT angiography (CCTA) could be avoided. Methods: GDF-15 was measured, using the assay on Cobas e801 (Roche Diagnostics), in 537 patients with chest pain and high-sensitivity cardiac troponin T concentrations ≤99th percentile. All participants underwent CAC scoring and CCTA. Obstructive CAD was defined as >50% lumen diameter narrowing. Associations of GDF-15 with obstructive CAD and 30-days revascularization were calculated by multivariable logistic regression adjusting for age, sex, smoking, hypertension, HbA1c, LDL-cholesterol, GFR and prior AMI. We also evaluated whether GDF-15 could improve sensitivity and negative predictive value (NPV) of CAC=0 for ruling out the presence of obstructive CAD. Results: The median (25th-75th percentile) age was 56 (49-65) years, 217 (40.4%) of the patients were women, 83 (15.5%) had obstructive CAD, and 49 (9.1%) had revascularization within 30 days. After multivariable adjustment, elevated GDF-15 (≥1200pg/mL) predicted obstructive CAD at baseline with OR (95%CI) of 2.23 (1.14-4.36), p=0.02. The OR (95%CI) for 30-days revascularization was 2.33 (1.08-5.03), p=0.03. For CAC=0, we observed a sensitivity (95%CI) and NPV (95%CI) of 94.0% (86.5%-98.0%) and 98.0% (95.3%-99.3%) in ruling out obstructive CAD. For patients having both CAC=0 and GDF-15 levels below median (<730pg/mL), sensitivity (95%CI) and NPV (95%CI) for obstructive CAD were 97.6% (91.6%-99.7%) and 98.7 (95.2%-99.8%), respectively. Conclusions: Elevated serum GDF-15 predicts obstructive CAD and 30 days revascularization among patients with chest pain, but without AMI. The combination of low GDF-15 levels and CAC=0 appears promising for the identification of low-risk patients, who can possibly be discharged without a full CCTA.

OC 46.4 Association of Growth Differentiation Factor-15 (GDF-15) with Thromboembolism and Mortality in Patients with Cancer: Findings from the Vienna Cats Study

OC 46.4 Association of Growth Differentiation Factor-15 (GDF-15) with Thromboembolism and Mortality in Patients with Cancer: Findings from the Vienna Cats Study

Hyperactive behaviour of growth differentiation factor- 15 (GDF-15) in conjunction with iron trafficking transporters and suppression of Nrf-2 gene in diabetes and metabolic syndrome.

Multiple parallel factors are frequently interrogated with various toxic radicals which are abundantly generated in the liver, heart, and pancreas in stress conditions. They are actively involved in the development of diabetes and metabolic aberrations. However, whether over-activation of GDF-15mRNA and influxes of iron-by-iron trafficking genes are directly suppressing the Nrf-2 gene in patients with diabetes and metabolic aberrations in context with undiagnosed individuals with diabetes and metabolic aberrations? Therefore, we have investigated inter and intra- related Zip8/14 mRNA, GDF-15mRNA, and Nrf-2 mRNA expressions in diabetes and metabolic syndrome as it is expected to be up to 134 million by 2045 in India. We recruited 120 subjects from the Department of Medicine, Endocrinology and Metabolic Clinic, All India Institute of Medical Sciences, New Delhi, India. Various investigations related to anthropometry, nutritional, hematological, biochemical, cytokine, and oxidative stress were measured in diabetes, metabolic syndrome, diabetes with metabolic aberration, and healthy controls. Relative expression of GDF-15, ZIP8, ZIP14, Nrf-2, and housekeeping genes was done in all subjects. Stress-responsive cytokines are highly expressed in patients with metabolic aberration with respect to body weight, IR, waist circumference, and fat mass. IL-1β, TNF-α, and IL-6 levels were significantly higher in metabolic syndrome, whereas Adiponectin levels were profoundly lower side. MDA levels were significantly raised in diabetes with metabolic syndrome while SOD activities were lowered (p = 0.001). GDF-15 mRNA expression was 1.79-fold upregulated in group III as compared with Group I while 2-threefold down-regulation of Nrf-2 expression was observed in diabetes with metabolic aberration groups. Zip 8 mRNA expressions were downregulated (p = 0.014), and Zip 14 mRNA expressions were upregulated (p = 0.06) in diabetes and metabolic aberrations. The association of GDF-15 and Nrf-2 mRNA expression was found contradictory and highly interlinked with ROS. Zip 8/14mRNA expressions were also dysregulated in diabetes and metabolic-associated complications.

Interrelation of growth/differentiation factor-15 level with laboratory and clinical and functional parameters of patients with coronary artery disease

Growth differentiation factor 15 (GDF-15) is a circulating protein that is associated with various pathological conditions.Aim. To study the relationship between the level of GDF-15 and labo­ratory, clinical and functional parameters of patients with coronary artery disease (CAD).Material and methods. All patients with coronary artery disease under­went a general clinical examination, coronary angiography, extrac­ranial artery ultrasound examination, echocardiography, deter­mi­nation of the serum level of GDF-15 (ng/ml) and matrix metal­lopro­teinase 9 (ng/ml). Statistical processing of the obtained results was carried out using the Statistica 10.0 software.Results. The study included 88 people (55 men and 33 women), 78 of whom were patients with an established diagnosis of CAD and 10 were healthy volunteers (control group). In the group of CAD patients, the median level of GDF-15 was 4,98 ng/ml [3,15; 8,24], while in the cont­rol group — 1,95 ng/ml [0,01; 2,45]. An association of GDF-15 con­centration with the age of patients was found (r=0,44; p<0,001). There was a direct correlation between the level of GDF-15 and interventricular septal thickness (r=0,33; p<0,05), heart failure stage (Strazhesko-Vasilenko classification) (r=0,23; p<0,05), the concentration of matrix metal­loproteinase 9 (r=0,24; p<0,05), carotid intima-media thickness (r=0,28; p<0,05), the number of coronary arteries that required revas­cularization during coronary artery bypass grafting (r=0,52; p<0,05), and multifocal atherosclerosis (r=0,23; p<0,05). In patients with athero­sclerotic lesions in 2 or 3 vascular beds, the level of GDF-15 was signifi­cantly higher than in patients with CAD (p<0,05).Conclusion. The results obtained demonstrate the value of GDF-15 as a potential marker of atherosclerotic vascular changes, the severity of myocardial hypertrophy, and the severity of heart failure.

Growth differentiation factor-15 and prediction of cancer-associated thrombosis and mortality: a prospective cohort study

BackgroundPatients with cancer are at increased risk of venous thromboembolism (VTE) and arterial thromboembolic/thrombotic events (ATEs). Growth differentiation factor-15 (GDF-15) improves cardiovascular risk assessment, but its predictive utility in patients with cancer remains undefined. ObjectivesTo investigate the association of GDF-15 with the risks of VTE, ATE, and mortality in patients with cancer and its predictive utility alongside established models. MethodsThe Vienna Cancer and Thrombosis Study (CATS)—a prospective, observational cohort study of patients with newly diagnosed or recurrent cancer—which was followed for 2 years, served as the study framework. Serum GDF-15 levels at study inclusion were measured, and any association with VTE, ATE, and death was determined using competing risk (VTE/ATE) or Cox regression (death) modeling. The added value of GDF-15 to established VTE risk prediction models was assessed using the Khorana and Vienna CATScore. ResultsAmong 1531 included patients with cancer (median age, 62 years; 53% men), median GDF-15 levels were 1004 ng/L (IQR, 654-1750). Increasing levels of GDF-15 were associated with the increased risks of VTE, ATE, and all-cause death ([subdistribution] hazard ratio per doubling, 1.16 [95% CI, 1.03-1.32], 1.30 [95% CI, 1.11-1.53], and 1.57 [95% CI, 1.46-1.69], respectively). After adjustment for clinically relevant covariates, the association only prevailed for all-cause death (hazard ratio, 1.21; 95% CI, 1.10-1.33) and GDF-15 did not improve the performance of the Khorana or Vienna CATScore. ConclusionGDF-15 is strongly associated with survival in patients with cancer, independent of the established risk factors. While an association with ATE and VTE was identified in univariable analysis, GDF-15 was not independently associated with these outcomes and failed to improve established VTE prediction models.

GDF-15 Is Associated with Poor Physical Function in Prefrail Older Adults with Diabetes.

Growth differentiation factor 15 (GDF-15) has been shown to be a metabolic and appetite regulator in diabetes mellitus (DM) and obesity. We aimed to investigate (i) the association between GDF-15 and DM with and without poor physical function independent of inflammation and (ii) the prediction model for poor physical function in prefrail older adults. A cross-sectional study of 108-prefrail participants ≥60 years recruited for multidomain interventions. Data was collected for demographics, cognition, function, frailty, nutrition, handgrip strength (HGS), short physical performance battery (SPPB), and gait speed. Serum concentrations of GDF-15, IL-6, and TNF-α were measured. GDF-15 was classified into tertiles (T1, T2, and T3), and its association was studied with DM and physical function (DM poor physical function, DM no poor physical function, no DM poor physical function, and no DM no poor physical function). Compared with T1, participants in T3 were significantly older, had a lower education level, had almost three times higher prevalence of DM, slower gait speed, longer chair-stand time, and lower SPPB scores. On multivariate analysis, the odds of having both DM and poor physical performance compared to having no DM and no poor physical performance were significantly higher in GDF-15 T3 vs. GDF-15 T1 (aOR 9.7, 95% CI 1.4-67.7; p = 0.021), and the odds of having DM no poor physical function compared to having no DM and no poor physical performance were significantly higher in GDF-15 T2 (aOR 12.7, 95% CI 1.1-143.7; p = 0.040) independent of BMI, IL-6, TNF-α, nutrition, physical function, education, age, and gender. The association of GDF-15 with DM-associated poor physical function is independent of inflammation in prefrail older adults. Its causal-association link needs to be determined in longitudinal studies.

Analyzing the Association of Visceral Adipose Tissue Growth Differentiation Factor-15 and MicroRNA in Type 2 Diabetes Mellitus.

Growth differentiation factor-15 (GDF-15) is involved in insulin resistance and diabetes. In this study, we determine the associations of GDF-15 with miR-181b-5p, miR-330-3p, mothers against decapentaplegic homolog 7 (SMAD7), and insulin resistance in visceral adipose tissue (VAT) and peripheral blood mononuclear cells (PBMCs) in type 2 diabetes mellitus (T2DM) patients. Sixty patients, equally divided into those with T2DM and non-diabetic controls, were recruited for gene expression analysis. Protein-protein interaction (STRING), target prediction (miRNet), and functional enrichment were conducted accordingly. Our study showed that VAT and PBMCs had similar expression profiles, where GDF-15 and miR-181b-5p were upregulated, whereas SMAD7 and miR-330-3p were downregulated. Serum GDF-15 could differentiate between T2DM and non-diabetic patients (P<0.001). Target prediction revealed a microRNA (miRNA)-messenger RNA regulatory network, transcription factors, and functional enrichment for the miRNA that suggested involvement in T2DM pathogenesis. VAT GDF-15 is associated with insulin resistance and is possibly regulated by miR-181b-5p, miR-330-3p, and SMAD7 in T2DM.

Prognostic value of Growth differentiation factors 15 in Acute heart failure patients with preserved ejection fraction.

There is an increasing proportion of hospitalized heart failure (HF) patients classified as HF with preserved ejection fraction (HFpEF) around the world. Growth differentiation factor 15 (GDF-15) is a promising biomarker in HFpEF prognostication; however, the majority of the existing data has been derived from the research on undifferentiated HF, whereas the studies focusing on HFpEF are still limited. This study aimed to determine the prognostic power of GDF-15 in the hospitalized patients with HFpEF in a Chinese cohort. We analysed the levels of serum GDF-15 in 380 patients hospitalized for acute onset of HFpEF measured by heart ultrasound at admission in a prospective cohort. The associations of GDF-15 with 1year risk of all-cause death and 1year HF readmission were assessed by the Cox proportional hazards model. Area under the receiver operating characteristic curves was used to compare predictive accuracy. GDF-15 was strongly correlated with 1year HF readmission and 1year all-cause death, with event rates of 24.8%, 40.0%, and 50.0% for 1year HF readmission (P<0.001), respectively, and with 11.2%, 13.6%, and 24.6% for 1year all-cause death (P=0.004) in the corresponding tertile, respectively. In the multivariate linear regression model, GDF-15 had a significantly negative correlation with haemoglobin (P=0.01) and a positive correlation with creatinine (P=0.01), alanine transaminase (P=0.001), and therapy of aldosterone antagonist (P=0.018). The univariate Cox regression model of GDF-15 showed that c-statistic was 0.632 for 1year HF readmission and 0.644 for 1year all-cause death, which were superior to the N-terminal pro-brain natriuretic peptide (NT-proBNP) model with c-statistics of 0.595 and 0.610, respectively. In the multivariable Cox regression model, GDF-15 tertiles independently predicted 1year HF readmission (hazard ratio 2.25, 95% confidence interval: 1.43-3.54, P<0.001) after adjusting for baseline Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) risk score, history of HF, NT-proBNP, and high-sensitivity cardiac troponin T. Compared with the model including all the adjusted variables, the model with the addition of GDF-15 improved predictive power, with c-statistic increasing from 0.643 to 0.657 for 1year HF readmission and from 0.638 to 0.660 for 1year all-cause death. In hospitalized patients with HFpEF, GDF-15 measured within 48h of admission is a strong independent biomarker for 1year HF readmission and even better than NT-proBNP. GDF-15 combined with the traditional indicators provided incremental prognostic value in this population.

Growth differentiation factor-15 predicts major bleeding, major adverse cardiac events and mortality in patients with end-stage kidney disease on haemodialysis: findings from the VIVALDI study.

Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular events and bleeding. Optimizing risk assessment of ESKD patients regarding the risk of thromboembolism and bleeding complications in comorbid conditions, including atrial fibrillation and coronary heart disease, is challenging. To improve risk prediction we investigated growth differentiation factor-15 (GDF-15), a promising cardiovascular biomarker, and its relation to adverse outcomes. In this prospective, multicentre, population-based cohort study, GDF-15 was measured in 594 ESKD patients on haemodialysis (median age 66years, 38% female), who were followed up for a median of 3.5years. The association of GDF-15 with major bleeding, arterial thromboembolism, major adverse cardiac events (MACE) and death was analysed within a competing risk framework. Further, we evaluated the additive predictive value of GDF-15 to cardiovascular and death risk assessment. GDF-15 levels were in median 5475ng/l (25th-75th percentile 3964-7533) and independently associated with major bleeding {subdistribution hazard ratio [SHR] 1.31 per double increase [95% confidence interval (CI) 1.00-1.71]}, MACE [SHR 1.47 (95% CI 1.11-1.94)] and all-cause mortality [SHR 1.58 (95% CI 1.28-1.95)] but not arterial thromboembolism [SHR 0.91 (95% CI 0.61-1.36)]. The addition of GDF-15 to the HAS-BLED score significantly improved discrimination and calibration for predicting major bleeding [C-statistics increased from 0.61 (95% CI 0.52-0.70) to 0.68 (95% CI 0.61-0.78)]. Furthermore, we established an additive predictive value of GDF-15 beyond current risk models for predicting MACE and death. GDF-15 predicts the risk of major bleeding, cardiovascular events and death in ESKD patients on haemodialysis and might be a valuable marker to guide treatment decisions in this challenging patient population.

Abstract 14368: Growth Differentiation Factor-15 in Heart Failure Across Body Mass Index Categories: The PREHOSP-CHF Study

Introduction: Growth differentiation factor-15 (GDF-15), a stress-responsive member of the transforming growth factor ꞵ cytokine superfamily is an independent prognostic predictor in patients with heart failure (HF). GDF-15 has been also reported to be associated with cardiac cachexia and malnutrition. However the association of GDF-15 and prognosis in patients with HF according to body mass index (BMI) is unclear. Methods: The PREHOSP-CHF study is a multicenter prospective cohort study among patients with HF. A total of 1,024 patients (mean age, 75.5 years, 58.7% male) were included in the analyses. Serum levels of GDF-15, as well as N-terminal pro brain natriuretic peptide (NT-proBNP), high sensitivity troponin I (hs-cTnI), and high sensitivity C-reactive protein (hs-CRP), were measured. We divided the patients into 3 groups based on the tertile of BMI: low (≤19.9), middle (19.9&lt;, ≤23.4), and high (&gt;23.4). Results: The low BMI group were older, and had more female, HF with preserved ejection fraction (≥50%), and NYHA 3/4. NT-proBNP levels were higher in the low group, but hs-cTnI and hs-CRP were comparable between the 3 subgroups. Median GDF-15 levels in the low, middle and high groups were 2271, 2264, and 1888 pg/ml, respectively. During 2 years follow-up, all-cause death and major adverse cardiovascular events (MACE: cardiovascular death and HF hospitalization) occurred in 111 and 130 in the low group, 66 and 132 in the middle group, and 34 and 88 in the high group. After adjustment for clinical confounders and cardiac biomarkers, higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the entire cohort. BMI subgroup analysis revealed that higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the middle and high groups, but not in the low group (Figure). Conclusions: Among HF, higher GDF-15 was significantly associated with all-cause death and MACE especially in the middle and high BMI groups.

Relationship Between Plasma Growth Differentiation Factor 15 Levels and Complications of Type 2 Diabetes Mellitus: A Cross-sectional Study

ObjectiveOur aim in this study was to identify the associations between growth differentiation factor 15 (GDF15) and type 2 diabetes mellitus (T2DM) complications in a community-based population in China. MethodsBased on a cross-sectional study registered in the National Basic Public Health Service for disease management of Changshu in China, a total of 1,689 T2DM patients were enrolled and tested further for plasma GDF15 levels. Macrovascular (cardiovascular disease and diabetic foot) and microvascular (diabetic kidney disease [DKD], diabetic retinopathy, and neuropathy) complications were evaluated. Logistic regression models were conducted to identify the associations of GDF15 with the risk of diabetes complications, and linear regression models were used to assess relationships between GDF15 and other clinical features. ResultsOverall, 459 of the 1,689 T2DM patients (27.18%) had complications. GDF15 levels were significantly higher in patients with any type of complication compared with their counterparts. With each standard deviation increase of base 10 logarithms of GDF15 (lg-GDF15), the risk of overall complications increased by 1.17-fold (95% confidence interval [CI], 1.03 to 1.32). In contrast to macrovascular complications, associations of GDF15 with microvascular complications appeared to be stronger (adjusted odds ratio [OR], 1.24; 95% CI, 1.08 to 1.43), especially for DKD (adjusted OR, 1.51; 95% CI, 1.19 to 1.93). Subgroup analyses showed that the strength of association between GDF15 and complications varied by distinct age and T2DM duration subgroups. Patients with 2 or more types of complications had higher levels of GDF15 than those with fewer types of complications. Also, linear relationships were identified between GDF15 and several liver and kidney function indices. ConclusionHigher GDF15 levels were associated with T2DM complications, especially DKD. GDF15 may serve as a biomarker for monitoring the deterioration of T2DM.

Integrated analyses of growth differentiation factor-15 concentration and cardiometabolic diseases in humans.

Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW pFDR = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.

GDF-15: A Potential Biomarker and Therapeutic Target in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a rheumatic disease. Growth differentiation factor 15 (GDF-15) is a member of transforming growth factor-β superfamily. To date, association of GDF-15 with SLE pathogenesis is not clarified. This study discussed GDF-15 serum levels and gene polymorphisms in SLE patients and lupus mouse model further demonstrated the role of GDF-15 in lupus development. We conducted two independent case-control studies for SLE patients. One is to evaluate serum levels of GDF-15 in 54 SLE patients and 90 healthy controls, and the other one is to analyze gene polymorphisms of GDF-15 in 289 SLE patients and 525 healthy controls. Serum levels of GDF-15 were detected by ELISA. GDF-15 gene polymorphisms (rs1055150, rs1058587, rs1059519, rs1059369, rs1227731, rs4808793, and rs16982345) were genotyped by the Kompetitive Allele-Specific PCR (KASP) method. Addition of recombinant GDF-15 into pristane-induced lupus mice evaluated histological and serological changes. Results showed that serum levels of GDF-15 were overexpressed in SLE patients and associated with disease activity. Polymorphisms rs1055150, rs1059369, rs1059519, and rs4808793 of GDF-15 gene were related to SLE risk. Lupus mice showed splenomegaly, severe histological scores, and high levels of autoantibodies [antinuclear antibodies (ANA) and total immunoglobulin G (IgG)], whereas administration of GDF-15 into lupus mice reduced the histological changes. Percentages of CD8+, CD11b+, CD19+, CD11C+ cells, TH2 cells, and pro-inflammatory cytokines (IL-1β, IL-2, IL-4, IL-21, and IL-22) were reduced after GDF-15 treatment in lupus mice. In conclusion, GDF-15 was related to lupus pathogenesis and inhibited lupus development.

IDF21-0383 Circulating GDF15 Predicted Mortality in Aging Chinese People with Type 2 Diabetes: Findings from Da Qing Diabetes Study

Background: Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. In people with type 2 diabetes, GDF15 is elevated and related to diabetic complications, such as diabetic retinopathy, and diabetic nephropathy. While the association of GDF15 and major adverse cardiovascular events (MACE) is not significant after adjustment of cardiovascular risk factors. A Mendelian randomization study also reported that GDF15 was not associated with type 2 diabetes and coronary artery disease risk factors. Therefore, the relationship between GDF15 and cardiovascular diseases in people with type 2 diabetes still need more studies to confirm. Aim: This study aims to investigate the relationship between circulating GDF15 and mortality including all-cause, cardiovascular, and cancer death in Chinese aging people with type 2 diabetes using the long-term follow-up data of the Da Qing Diabetes Study. Method: A total of 510 subjects from the Da Qing Diabetes Study with type 2 diabetes were enrolled in the present study. The circulating GDF15 in 2006 or 2009 were assessed. Outcomes of all-cause, cardiovascular, and cancer mortality were followed in 2016 (mean follow-up of 7.5 years). Time-to-event survival curves for each outcome were created using the cumulative incidence method, and comparisons between the groups were performed with log-rank tests. Cox proportional hazards regression was used for the estimation of hazard ratios (HRs) and their 95% confidence intervals (CIs) for death. Results: At the end of the follow-up, 143 (28.0%) subjects died and 54.5% (78/143) were cardiovascular death. The cumulative incidence of all-cause death in the third tertile group was higher than that in the lowest level group (58.6% [95% CI 43.7 – 73.6] vs 19.6% [95% CI 12.7 – 26.5], log-rank p < 0.0001). Compared to the first tertile group of GDF15, the risk of all-cause death (HR = 3.27, 95% CI [1.90 – 5.64]), and cardiovascular death (HR = 3.11, 95% [1.45 – 6.67]) in the third tertile group increased more than two folds, even after adjustment of age, sex, smoking, SBP, LDL-c, HbA1c, duration of diabetes, and CVD history. Increased GDF15 level (per 1 SD increase) related to a higher risk of cancer death in all subjects (HR = 2.25, 95%CI [1.34 – 3.80]) and those without CVD (HR = 2.88, 95%CI [1.59 – 5.24]) after adjustment of traditional risk factors. Discussion: In the present study, an elevated level of GDF15 is related to the higher risk of all-cause, cardiovascular, and cancer death in Chinese aging people with type 2 diabetes. The results of all-cause and cardiovascular death were consistent regardless of CVD history. Expression of GDF15 was upregulated in response to many stimuli, and involved in cell stress, such as responding to ischemia in cultured cardiomyocytes. The substantial mechanism may be the protective role of GDF15 in the disease process, including insulin resistance regulation, anti-apoptosis, and anti-inflammation. These data provide more insight into the prevention of diabetic complications especially the primary and secondary prevention of cardiovascular death. The predictive power of GDF15 deserves more attention.

Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study.

Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. We evaluated 10,570 participants free of HF at Visit 3 (1993-1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. Among a total of 10,570 individuals (mean age of 60.0years, 54% women, 27% black adults), elevated GDF-15 (≥75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p<0.0001). During 23years of follow-up, there were 2429 incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction= 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (ΔC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.0001). In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes.

Serum markers of biological ageing provide long-term prediction of life expectancy-a longitudinal analysis in middle-aged and older German adults.

lifestyle behaviours and chronic co-morbidities are leading risk factors for premature mortality and collectively predict wide variability in individual life expectancy (LE). We investigated whether a pre-selected panel of five serum markers of biological ageing could improve predicting the long-term mortality risk and LE in middle-aged and older women and men. we conducted a case-cohort study (n = 5,789 among which there were 2,571 deaths) within the European Prospective Investigation into Cancer-Heidelberg cohort, a population cohort of middle-aged and older individuals, followed over a median duration of 18years. Gompertz models were used to compute multi-adjusted associations of growth differentiation factor-15, N-terminal pro-brain natriuretic peptide, glycated haemoglobin A1c, C-reactive protein and cystatin-C with mortality risk. Areas under estimated Gompertz survival curves were used to estimate the LE of individuals using a model with lifestyle-related risk factors only (smoking history, body mass index, waist circumference, alcohol, physical inactivity, diabetes and hypertension), or with lifestyle factors plus the ageing-related markers. a model including only lifestyle-related factors predicted a LE difference of 16.8 [95% confidence interval: 15.9; 19.1] years in men and 9.87 [9.20; 13.1] years in women aged ≥60years by comparing individuals in the highest versus the lowest quintiles of estimated mortality risk. Including the ageing-related biomarkers in the model increased these differences up to 22.7 [22.3; 26.9] years in men and 14.00 [12.9; 18.2] years in women. serum markers of ageing are potentially strong predictors for long-term mortality risk in a general population sample of older and middle-aged individuals and may help to identify individuals at higher risk of premature death, who could benefit from interventions to prevent further ageing-related health declines.

Ageing-related markers and risks of cancer and cardiovascular disease: a prospective study in the EPIC-Heidelberg cohort

Biological age is an important risk factor for chronic diseases. We examined the associations between five markers of unhealthy ageing; Growth Differentiation Factor-15 (GDF-15), N-terminal pro-brain natriuretic peptide (NT-proBNP), glycated hemoglobin A1c (HbA1C), C-Reactive Protein (CRP) and cystatin-C; with risks of cancer and cardiovascular disease (CVD). We used a case-cohort design embedded in the EPIC-Heidelberg cohort, including a subcohort of 3792 participants along with 4867 incident cases of cancer and CVD. Hazard ratios (HRs) were computed and the strongest associations were used to build weighted multi-marker combinations, and their associations with cancer and CVD risks were tested. After adjusting for common confounders, we observed direct associations of GDF-15 with lung cancer risk, NT-proBNP with breast, prostate and colorectal cancers, HbA1C with lung, colorectal, and breast cancer risks, and CRP with lung and colorectal cancer risks. An inverse association was observed for GDF-15 and prostate cancer risk. We also found direct associations of all 5 markers with myocardial infarction (MI) risk, and of GDF-15, NT-proBNP, CRP and cystatin-C with stroke risk. A combination of the independently-associated markers showed a moderately strong association with the risks of cancer and CVD (HRQ4-Q1 ranged from 1.78[1.36, 2.34] for breast cancer, when combining NT-proBNP and HbA1C, to 2.87[2.15, 3.83] for MI when combining NT-proBNP, HbA1C, CRP and cystatin-C). This analysis suggests that combinations of biomarkers related to unhealthy ageing show strong associations with cancer risk, and corroborates published evidence on CVD risk. If confirmed in other studies, using these biomarkers could be useful for the identification of individuals at higher risk of age-related diseases.