Abd-Elmawgood EA, Hassan MH, Abd-Elbaseer KA, Ibrahem MH, Yousef KMH, Bakri AH. Circulating levels of growth differentiation factor-15 and its genetic variants -3148C>G (rs4808793) in pediatric cardiac patients. World J Clin Pediatr 2026; 15(2): 117283 [DOI: 10.5409/wjcp.v15.i2.117283]
Corresponding Author of This Article
Mohammed H Hassan, MD, Professor, Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Qena University, Elsafwa School Street, Qena 83523, Egypt. mohammedhosnyhassaan@yahoo.com
Research Domain of This Article
Medicine, Research & Experimental
Article-Type of This Article
Case Control Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Eman Ahmed Abd-Elmawgood, Khaled Abdalla Abd-Elbaseer, Mona Hashem Ibrahem, Ali Helmi Bakri, Department of Pediatrics, Faculty of Medicine, Qena University, Qena 83523, Egypt
Mohammed H Hassan, Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Qena University, Qena 83523, Egypt
Mohammed H Hassan, Department of Pathology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia
Khaled Mohammed Hassan Yousef, Department of Biochemistry, Faculty of Pharmacy, Qena University, Qena 83523, Egypt
Co-first authors: Eman Ahmed Abd-Elmawgood and Mohammed H Hassan.
Author contributions: Abd-Elbaseer KA, Abd-Elmawgood EA, Hassan MH, Yousef KMH, and Bakri AH conceived and designed the project; Abd-Elmawgood EA, Hassan MH, Abd-Elbaseer KA, Ibrahem MH, Yousef KMH, and Bakri AH collected data, analyzed, and interpreted the data; Abd-Elmawgood EA and Hassan MH drafted the manuscript. All authors have read and approved the final manuscript.
Institutional review board statement: This study was approved by the ethics committee of the Faculty of Medicine, Qena University, Qena, Egypt (No. SVU-MED-PED025-1-21-9-239).
Informed consent statement: Informed written consent was taken from the included participants or their caregivers for participation in the study and publication.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request, after obtaining the permission of our institute.
Corresponding author: Mohammed H Hassan, MD, Professor, Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Qena University, Elsafwa School Street, Qena 83523, Egypt. mohammedhosnyhassaan@yahoo.com
Received: December 4, 2025 Revised: December 22, 2025 Accepted: February 3, 2026 Published online: June 9, 2026 Processing time: 161 Days and 1.6 Hours
Abstract
BACKGROUND
Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine. Though less extensively studied in children than in adults, recent evidence highlights the potential value of GDF-15 in pediatric cardiology.
AIM
To assess the serum GDF-15 levels and the genetic profile of GDF-15 rs4808793 among children with cardiac diseases.
METHODS
This case-control study included 100 pediatric cardiac patients and 50 healthy controls. GDF-15 rs4808793 (-3148C>G) single-nucleotide polymorphism was tested via restriction fragment length polymorphism-polymerase chain reaction technique, and serum GDF-15 was measured using the enzyme-linked immunosorbent assay technique.
RESULTS
Of the 69 children with various types of congenital heart diseases (CHD), 14 patients had rheumatic heart disease, and 17 had cardiomyopathy. About 50% of patients had heart failure. Significantly higher mean serum GDF-15 among patients compared to the controls, P < 0.001. Heart failure patients had significantly higher serum GDF-15 than those who didn’t, P < 0.001. CC-genotype and C-allele of rs4808793 were significantly more frequent among cardiac patients compared to the controls (P = 0.002). C-allele of rs4808793 was associated with an increased CHD risk (odds ratio = 2.812, 95% confidence interval: 1.648-4.799).
CONCLUSION
GDF-15 is a promising biomarker in predicting congenital heart disease and heart failure in children. The genetic variants of GDF-15 (rs4808793) were significantly associated with CHD risk.
Core Tip: Growth differentiation factor-15 (GDF-15) is increasingly recognized as a valuable biomarker and potential genetic contributor in pediatric cardiac disorders. Significantly elevated serum GDF-15 levels are observed in children with heart failure, reflecting disease severity and progression. Additionally, the higher prevalence of the C-allele of the GDF-15 rs4808793 polymorphism among patients with congenital heart disease supports a genetic susceptibility component. Together, these findings highlight the potential role of GDF-15 in development and progression of pediatric cardiovascular diseases.
Citation: Abd-Elmawgood EA, Hassan MH, Abd-Elbaseer KA, Ibrahem MH, Yousef KMH, Bakri AH. Circulating levels of growth differentiation factor-15 and its genetic variants -3148C>G (rs4808793) in pediatric cardiac patients. World J Clin Pediatr 2026; 15(2): 117283
Cardiovascular disease is a leading cause of morbidity and mortality worldwide, and an increasing body of evidence underscores the importance of fetal and pediatric programming for cardiovascular health and disease. Fortunately, in recent years, the field of pediatric cardiology has witnessed an impressive increase in diagnostic and therapeutic possibilities[1-3]. Growth differentiation factor-15 (GDF-15), also known as serum macrophage inhibitory cytokine-1, is part of the transforming growth factor beta superfamily and plays a role in various physiological and pathological processes. Concentrations can rise in response to cellular stress, as observed in cardiac and renal failure, chronic liver disease, and chronic inflammatory diseases[4,5]. GDF-15 is expressed weakly in heart muscle under normal physiology; however, the production of GDF-15 is upregulated in cardiomyocytes following ischemia-reperfusion injury. The mechanical stress and injury on the myocardium induce the secretion and release of GDF-15[6]. GDF-15 is thus considered a myokine and cardiokine[7].
The human GDF-15 is encoded by a gene located on chromosome 19, in which eight polymorphisms, in particular single-nucleotide polymorphisms (SNPs) associated with promoter activity, including -3148C>G (rs4808793), were proven to regulate its serum level[8]. The rs4808793 polymorphism of GDF-15 results from the replacement of the G allele with the C allele in the upstream region of GDF-15[9]. Despite its emerging recognition as a biomarker in cardiovascular diseases, the precise role of GDF-15 in cardiac pathophysiology remains poorly understood[10]. So the present research aimed to assess the serum levels of GDF-15 and its gene polymorphism (GDF-15 rs4808793 (-3148C>G) SNP) in pediatric patients with different cardiac diseases, e.g., congenital heart disease (CHD), rheumatic heart disease, cardiomyopathy, and heart failure. Also, to correlate serum GDF-15 and the genetic variants with the clinical and echocardiographic data of the included patients.
MATERIALS AND METHODS
This is a cross-sectional, case-control, hospital based study carried out on 100 pediatric cardiac patients (group A included 69 children with CHD; group B included 14 children with rheumatic heart disease; group C included 17 children with cardiomyopathy) enrolled from pediatric intensive care unit, outpatient pediatric cardiology clinics, and pediatric department of Qena University Hospital, Egypt, between August 2021 and September 2022. They were comparable with 50 healthy age and sex-matched controls (group D), who were included. Controls were recruited from children attending routine outpatient visits and well-child check-ups, with no history or clinical evidence of cardiac disease, chronic illness, or inflammatory conditions. Any pediatric patient confirmed to have cardiac disease aged from 3 months to 18 years old was included in the study. Patients with other comorbidities, e.g., renal, neurological, respiratory, hepatic, autoimmune, gastrointestinal, hematological, or oncological diseases, were excluded from the study.
The current research was conducted in accordance with the Declaration of Helsinki. Prior to starting the study, it was approved by the local Ethics Committee of the Faculty of Medicine, Qena University, Qena, Egypt, with the ethical approval code: No. SVU-MED-PED025-1-21-9-239. Informed written consents were obtained from the parents or the caregivers of the included pediatric patients. Sample size was adjusted to achieve 80% power and 5% confidence of significance (type I error). In addition to general examination, anthropometric measurements (to assess physical development), and cardiac examination using Modified Ross classification (to assess pediatric patients with heart failure) of heart failure[11], echocardiographic evaluations were performed for all participants using a phased array spectrum probe 6 MHz, vivid S5. Using two-dimensional imaging to delineate anatomy, valve morphology, the relative size of all cardiac chambers, ventricular contractility, and gives a rough assessment of function through wall motion, and detects if there are anatomic abnormalities. The following parameters were measured: Ejection fraction, fractional shortening, left ventricular end diastolic diameter, left ventricular end systolic diameter (LVESD), pulmonary artery pressure, and interventricular septum. Echocardiography was performed through period of admission for admitted cases and at the time of presentation for outpatient cases.
Blood samples, biochemical and genetic assays
From each participant, 5 mL venous blood was withdrawn and separated into two parts. The first part (2 mL) was evacuated into ethylenediaminetetraacetic acid-containing tubes and was kept directly at -80 °C and will be used for genetic assays. The second part (3 mL) was transferred into plain tubes and allowed to clot at 37 °C for 30 minutes, then centrifuged for 15 minutes at 822 g. The separated sera were evacuated into 1 mL cryotubes and stored at -20 °C until the time of biochemical assays of GDF-15. Serum GDF-15 levels were measured using commercially available assay kits based on the sandwich enzyme-linked immunosorbent assay technique, supplied by Chongqing Biospes Co., Ltd., Chongqing, China (No. BEK1290).
For genetic analysis, extraction of the genomic DNA from the whole ethylenediaminetetraacetic acid blood samples was performed using the G-spinTM total DNA extraction kit supplied by iNtRON Biotechnology Inc., Korea, according to the manufacturer’s protocol. Restriction fragment length polymorphism-polymerase chain reaction (PCR) technique was used for genotyping of GDF-15 rs4808793 (-3148C>G) SNP using the following forward and reverse primers’ sequences: F5’-GCAACAGAGCGAGACTCCA-3’ and R5’-CCACGCCGGTCGGATTAAAACT-3’[9,12]. The PCR condition was as follows: 10 minutes at 94 °C as initial denaturation, then 53 cycles of the following thermal profile (94 °C for 30 seconds, 65 °C for 30 seconds, and 72 °C for 30 seconds), then 5 minutes for the last extension. The PCR amplification products will be at 665 bp (Figure 1A). A restriction enzyme supplied by New England Biolabs (MA, United States) (No. R0514S) was used to digest the PCR amplification products, and the final products of digestion were separated on 2% agarose gels stained with ethidium bromide and were visualized using ultraviolet light. The interpretation of the genotypes based on the digestion products band sizes is as follows: An intact single band at 665 bp indicates a wild CC genotype, two distinct bands at 422 bp and 243 bp indicate a homozygous variant GG genotype, while three distinct bands at 665 bp, 422 bp, and 243 bp indicate heterozygous variant CG genotype (Figure 1B).
Figure 1 Polymerase chain reaction amplification and digestion products of growth differentiation factor-15 rs4808793 (-3148C>G) single-nucleotide polymorphism using the restriction fragment length polymorphism- polymerase chain reaction technique.
A: Lane 1 and 6 referred to 100-bp DNA ladder; lanes 2, 3, 4, and 5 showed undigested amplified polymerase chain reaction product bands at 665 bp; B: Lanes 2, 4, 6, 7, and 8 referred to wild homozygous (CC) genotype with 665 bp bands; lane 3 referred to homozygous variant (GG) genotype with 422 bp, and 243 bp bands; lane 5 referred to heterozygous variant (CG) genotype with 665 bp, 422 bp, and 243 bp bands.
Statistical analysis
Date entry and data analysis were done using SPSS version 22 (Statistical Package for Social Science). Data were presented as numbers, percentages, means, and standard deviation. The χ2 test and Fisher’s Exact test were used to compare qualitative variables. An independent t-test (unpaired t-test) was used to compare quantitative variables between two different groups, and the one-way analysis of variance test for more than two groups. A paired samples t-test was done to compare quantitative variables. Pearson correlation was used to measure the correlation between quantitative variables. The studied SNP followed the Hardy-Weinberg equation. By calculating the area under the curve (AUC) [95% confidence interval (CI)], sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), a receiver operating characteristic (ROC) curve was created to determine the ideal cutoff point for serum GDF-15 (pg/mL) in the diagnosis of CHD and heart failure. Level of significance was considered at P < 0.05.
RESULTS
Demographic, clinical, and echocardiographic data of the study groups
The included pediatric cardiac patients were 100 participants, 69 patients have CHD [20 with ventricular septal defect, 20 with atrial septal defect, 18 have patent ductus arteriosus, and 11 with tetralogy of fallot (TOF)], 14 patients have rheumatic heart diseases (7 with mitral regurgitation, 2 with pulmonary regurgitation, 2 have mitral valve prolapse and stenosis, 2 have tricuspid regurgitation, and one patient have mixed aortic regurgitation and aortic stenosis), and 17 patients have cardiomyopathy (10 patients have dilated cardiomyopathy, 5 with hypertrophic cardiomyopathy, and 2 with secondary cardiomyopathy).
The median age of cases was 1.25 years (interquartile range = 0.67-5), with no significant difference in comparison with controls, 4.5 years (interquartile range = 0.73-8), P-value = 0.100. The percentage of males among cases was 46% and 38% in controls, but the percentage of females among cases was 54% and among controls was 62%, with no significant differences between the two groups (P-value = 0.351). There was 52% of parental consanguinity among cases and 54% among controls, with a non-significant difference (P-value = 0.817). The mean body mass index (BMI) in cases was (16.18 ± 2.33 kg/m2) and in controls was (17.06 ± 1.91 kg/m2), with a P-value = 0.054.
Among the included cardiac patients, 44% have delayed physical development, and 42% have delayed mental development. About 50% of cases have heart failure, with Modified Ross class I presented in 24%, class II in 46%, class III in 24%, and class IV in 6%. Regarding echocardiographic data, the mean ejection fraction and fraction shortening were significantly lower among cases compared to the controls, and in heart failure patients compared to patients without heart failure, P < 0.05 for all. The median pulmonary artery pressure was significantly higher in cases compared to the controls, P = 0.001. There was a significantly increased mean value of LVESD among patients with heart failure compared to patients who didn’t have it, P = 0.037 (Table 1).
Table 1 Comparison between various echocardiographic parameters among the study groups, mean ± SD.
Circulating levels of GDF-15 and its correlation with echocardiographic parameters among the studied groups
There were significantly higher GDF-15 levels among cases, with a mean of 948.35 ± 386.29 pg/mL compared to the control group (249.48 ± 99.9 pg/mL), P < 0.001. The highest serum GDF-15 levels were among patients with cardiomyopathy and patients with rheumatic heart disease, and the lowest levels were among pediatric patients with CHD, P < 0.001. Although patients with TOF have significantly higher GDF-15 compared to patients with other CHD types, P < 0.001. Additionally, there were significantly higher mean GDF-15 serum levels among heart failure patients (1170 ± 292.55 pg/mL) when compared to patients without heart failure (726.7 ± 340.04 pg/mL), P < 0.001 (Table 2). There were insignificant differences regarding serum GDF-15 levels among patients with delayed physical or mental development compared to those who hadn’t in various groups of pediatric cardiac diseases, P > 0.05 for all. Among the included cases, there was a significant negative correlation between serum GDF-15 levels and ejection fraction (r = -0.323, P = 0.007), but it was positively correlated with pulmonary artery pressure (r = 0.379, P = 0.001). There were no other significant correlations between serum levels of GDF-15 and other echocardiographic parameters, P > 0.05 for all. By using ROC-curve analysis, serum GDF-15 level can predict pediatric patients with CHD vs other cardiac diseases among pediatric patients at cut off > 442 pg/mL, with the sensitivity, specificity, PPV, and NPV were 82.6%, 96%, 88.5% and 61.5%, respectively, and AUC = 0.976 (Figure 2A). Additionally, serum GDF-15 level can predict pediatric patients with heart failure of various etiologies at cut off > 902 pg/mL, with the sensitivity, specificity, PPV, and NPV were 88%, 74%, 77.2%, and 86%, respectively, and AUC = 0.750 (Figure 2B).
Figure 2 Receiver operator characteristics curve of serum growth differentiation factor-15 levels (pg/mL) among pediatric patients.
A: In predicting pediatric patients with congenital heart disease; B: In predicting heart failure among patients with cardiac diseases.
Table 2 Comparison of the serum growth differentiation-15 levels among the study groups, mean ± SD.
Distribution of various genotypes and alleles of GDF-15 rs4808793 (-3148C>G) SNP among the study groups
There was a significantly higher frequency of CC genotype and significantly lower GG genotype frequency among cases (36% and 11%, respectively) in comparison with the controls (10%, and 22% respectively), P = 0.002. Additionally, there was a significantly higher frequency of C-allele and significantly lower G-allele frequency among cases (62.5% and 37.5%, respectively) compared to the controls (44%, and 56% respectively), P = 0.002. This indicates that the GDF-15 rs4808793 (-3148C>G) SNP could be considered as a protective genetic factor against the development of cardiac diseases among children with an odds ratio = 2.121, 95%CI: 1.302-3.455 (Table 3). Similarly, when considering pediatric patients with CHD compared to the controls, GDF-15 rs4808793 (-3148C>G) SNP could be considered as a protective genetic factor with an odds ratio = 2.812, 95%CI: 1.648-4.799 (Table 4). In contrast, while analyzing GDF-15 rs4808793 (-3148C>G) SNP among pediatric patients with heart failure in comparison with those who haven’t, there were no significant differences, either in the genotype frequencies or in the allele frequencies among the two patient subgroups, as presented in Table 5, with P > 0.05. Also, the genotypes and allele frequencies of GDF-15 rs4808793 (-3148C>G) SNP among pediatric patients with other cardiac diseases (rheumatic heart disease, cardiomyopathy) in comparison with the controls revealed insignificant differences, P > 0.05. Also, there were insignificant differences regarding the values of serum GDF-15 among the included patients in terms of different genotypes of GDF-15 rs4808793 (-3148C>G) SNP, P > 0.05.
Table 3 Genotypes and allele frequencies of growth differentiation factor-15 rs4808793 (-3148C>G) single-nucleotide polymorphism among the study groups.
Table 4 Genotypes and allele frequencies of growth differentiation factor-15 rs4808793 (-3148C>G) single-nucleotide polymorphism among congenital heart diseases and controls.
Table 5 Genotypes and allele frequencies of growth differentiation factor-15 (rs4808793) single-nucleotide polymorphism among patients with and without heart failure.
Study groups
Variables
GDF-15 rs4808793 (-3148C>G) genotypes
GDF-15 rs4808793 (-3148C>G) alleles
CC
CG
GG
CC+CG
GG
CC
CG+GG
C
G
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
Pediatric cardiac patients with heart failure (n = 50)
16
32
27
54
7
14
43
86
7
14
16
32
34
68
59
59
41
41
Pediatric cardiac patients without heart failure (n = 50)
Although the value of serum GDF-15 in adults is well established, its function in children is still being studied. The current study aimed to evaluate the serum GDF-15 among a cohort of Egyptian children with various types of cardiac diseases with and without heart failure. Additionally, to explore the possible association of GDF-15 rs4808793 (-3148C>G) SNP genetic variants with the development and/or progression of heart diseases among the pediatric population.
Our findings revealed a relatively equal distribution of cardiac diseases among male and female children, suggesting that sex may not be a major determinant in the occurrence of pediatric cardiac diseases in our population sample. Several studies have reported varying gender distributions in pediatric cardiac diseases. For example, some researches have shown a slight male predominance in CHD, possibly due to sex linked genetic factors, or higher detection rates in males. A study by van der Linde et al[13] in a meta-analysis on CHD found a slightly higher prevalence in males than in females. Pugnaloni et al[14] reported similar findings. However, other studies, such as those conducted in certain Middle Eastern and South Asian populations, have reported no significant gender differences[15], aligning with our findings.
In the current study, parental consanguinity was reported among 52% of the included cases, with 69% of them diagnosed to have CHD, and in 54% of the controls. The high consanguinity rates are commonly reported in Middle Eastern and North African regions, where cultural practices often favor consanguineous marriages. Numerous studies have indicated a positive association between consanguinity and CHD, attributing it to the increased expression of autosomal recessive genes. For example, Becker et al[16], Bittles[17], and Shieh et al[18] have highlighted the role of consanguinity in elevating the risk of congenital malformations, including CHD. However, some population-based studies have found no significant difference in the consanguinity rates between affected and unaffected children, particularly when overall consanguinity in the population is uniformly high, which may explain our findings.
The findings of this study revealed lower mean BMI among pediatric cardiac patients compared to the controls, although not statistically significant, indicating possible subclinical nutritional or metabolic effects of cardiac conditions. This could reflect the impact of chronic illness on growth and nutritional status. Several reports, including those by Vaidyanathan et al[19], Medoff-Cooper et al[20], Zhang et al[21], and Lee et al[22], have shown that children with congenital or chronic cardiac conditions often experience growth retardation, lower BMI, and failure to thrive, particularly in those with cyanotic heart disease or congestive heart failure.
Regarding the developmental delays among the included pediatric cardiac patients, more than 40% have delayed physical and or mental delays, highlighting the neurodevelopmental and growth challenges in children with congenital or acquired heart diseases. These delays could be attributed to the chronic hypoxemia and increased metabolic demands with inadequate nutritional intake. Several studies were in accordance with these findings[23-25].
In the present research, 50% of the included patients have heart failure, with 70% have class I to class II and 30% have class III-IV. It was reported that heart failure occurs in 25%-50% of children with significant structural heart defects or cardiomyopathies, especially those with volume or pressure overload. The Modified Ross classification remains a reliable tool for assessment[26]. Hassan et al[27] reported 61.7% have mild heart failure, 28.3% have moderate, and 10% of cases have severe heart failure among the included children with severe lower respiratory tract infection, with a similar distribution of heart failure classes observed in the present study. As regards the echocardiographic data of the included patients, they have decreased ejection fraction and fraction shortening reflecting systolic dysfunction, and elevated pulmonary artery pressure indicating pulmonary vascular involvement, with increased LVESD suggesting ventricular dilation and remodeling. These results were similar to previous studies[28-31]. GDF-15, a member of the transforming growth factor-beta cytokine family, is upregulated in cardiomyocytes in response to ischemia, pressure overload, oxidative stress, and inflammation[32]. In the present study, there were elevated serum GDF-15 levels among pediatric cardiac patients, with more increased levels among those with heart failure. Kronenberger et al[33] reported that circulating GDF-15 among children with any form of cardiac dysfunction was 2-4 × higher than in healthy controls. Zhou et al[34] observed significantly elevated GDF-15 in children with heart failure, and it was positively correlated with disease severity.
In the current work, there were significantly higher serum GDF-15 levels among children with rheumatic heart disease, cardiomyopathy, or TOF than among other types of CHD. Rheumatic heart disease and cardiomyopathy involve direct myocardial inflammation and remodeling, leading to greater GDF-15 expression. CHD patients, unless complicated by cyanotic heart disease or heart failure, may have less myocardial stress, explaining lower GDF-15 levels. TOF is associated with chronic hypoxemia and right ventricular pressure overload, which can upregulate GDF-15 expression. Karakuş-Epçaçan et al[35] observed higher serum GDF-15 among children with acute rheumatic fever at the time of diagnosis, with return to similar levels as healthy children after treatment. Elganzory et al[36] reported significantly higher serum GDF-15 levels among children with CHD, particularly those with TOF. Additionally, Norozi et al[37] reported higher GDF-15 among children with TOF, particularly those who have heart failure, and it was positively correlated with N-terminal-pro brain natriuretic peptide levels. No previous studies could be traced in the literature regarding the serum GDF-15 levels among children with cardiomyopathy. In the cardiomyopathy mouse model, GDF-15 was upregulated in dilated, not hypertrophic cardiomyopathy[38].
In the current research, there were no significant differences in GDF-15 levels between children with or without physical or mental developmental delays across different cardiac diseases, highlighting the lack of association of GDF-15 with neurodevelopmental status in pediatric cardiac patients. Additionally, GDF-15 levels were negatively correlated with ejection fraction, supporting its role as a marker of systolic dysfunction, and positively correlated with pulmonary artery pressure, highlighting its sensitivity to pulmonary vascular stress. Marino et al[39] reported that neurodevelopmental outcomes in children with CHD are more strongly associated with perioperative factors and cerebral blood flow than with biomarkers like GDF-15. Previous studies have reported a lack of significant association between GDF-15 and physical or neurodevelopmental growth[40,41]. In contrast, other studies confirm this association[36,42,43]. Similarly, Tantawy et al[44] and Nair and Gongora[45] have reported a negative correlation between GDF-15 and ejection fraction. Tantawy et al[44], Li et al[46], and El Amrousy et al[47] noticed a significant positive correlation between GDF-15 and pulmonary hypertension among children with CHD.
In the present study, the diagnostic utility of serum GDF-15 in predicting pediatric cardiac patients with CHD vs other cardiac diseases and in predicting heart failure of various etiologies among children were based on ROC-curve analysis and revealed moderate discriminating ability of GDF-15 in diagnosing children with CHD with AUC = 0.976 at cutoff > 442 pg/mL and excellent discriminative power in detecting heart failure among children with AUC = 0.750 at cutoff > 902 pg/mL, indicating the important role of GDF-15 as a diagnostic marker in pediatric cardiac setting. Similarly, Chen et al[48] reported the utility of GDF-15 in diagnosing CHD associated with heart failure with a sensitivity 91.25%, specificity 74%, and AUC = 0.821.
The preliminary results of the current work revealed the important role of GDF-15 rs4808793 (-3148C>G) SNP in the genetic susceptibility to cardiac diseases in children, particularly CHD. The G-allele might serve a protective function, while the C-allele is associated with greater disease risk. This further emphasizes that GDF-15 promoter polymorphism affects early cardiac development, potentially through dysregulated GDF-15 expression during embryogenesis or later response to hemodynamic stress in utero. The relation between GDF-15 rs4808793 (-3148C>G) genetic polymorphism and cardiovascular diseases was investigated among the adult population with controversial results, but no previous research could be traced in the literature regarding its possible role in the pediatric population. Chen et al[49] failed to confirm an association between GDF-15 genetic polymorphism and coronary artery disease among the Chinese population. While Chen et al[49] reported a significant association of the CC genotype and C-allele with myocardial infarction among the Han population of the Taiyuan area. The single-center cross-sectional nature of the study, the heterogeneous age distribution, the limited relevance of GDF-15 for its proposed clinical use as a biomarker, with a relatively small sample size, and the lack of follow-up serum GDF-15 assays were the main limitations of the current study.
CONCLUSION
The current study provides preliminary evidence of possible involvement of GDF-15 and its genetic variants in paediatric cardiac diseases, specifically CHD and heart failure. More future research involving larger, multi-center studies to validate our findings is needed and to fully understand the molecular pathways involving GDF-15 and how its genetic variation can be leveraged for better clinical decision-making in children with cardiac diseases.
Atar R, Dayer D, Jalalifar MA, Keikhaei B, Asadi ZTN. The rs4808793 polymorphism of GDF-15 associates with significantly elevated ferritin in both thalassemia major and thalassemia intermedia.Clin Cancer Investig J. 2021;10:117-121.
[PubMed] [DOI] [Full Text]
Ferreira R, Velho TR, Pereira RM, Pedroso D, Draiblate B, Constantino S, Nobre Â, Almeida AG, Moita LF, Pinto F. Growth Differentiation Factor 15 as a Biomarker for Risk Stratification in the Cardiothoracic Surgery Intensive Care Unit.Biomolecules. 2024;14:1593.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 3][Reference Citation Analysis (0)]
Bakri AH, Hassan MH, Abd-Elbaseer KA, Sayed MA, Abdallah AAM, Abd-Elmawgood EA. Association of macrophage migration-inhibitory factor gene and growth differentiation factor 15 gene polymorphisms and their circulating levels with respiratory distress syndrome among preterm neonates.Clin Exp Pediatr. 2025;68:680-689.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in RCA: 3][Reference Citation Analysis (0)]
Becker SM, Al Halees Z, Molina C, Paterson RM. Consanguinity and congenital heart disease in Saudi Arabia.Am J Med Genet. 2001;99:8-13.
[PubMed] [DOI] [Full Text]
Medoff-Cooper B, Irving SY, Hanlon AL, Golfenshtein N, Radcliffe J, Stallings VA, Marino BS, Ravishankar C. The Association among Feeding Mode, Growth, and Developmental Outcomes in Infants with Complex Congenital Heart Disease at 6 and 12 Months of Age.J Pediatr. 2016;169:154-9.e1.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 76][Cited by in RCA: 94][Article Influence: 9.4][Reference Citation Analysis (0)]
Provost S, Fourdain S, Vannasing P, Tremblay J, Roger K, Caron-Desrochers L, Hüsser A, Paquette N, Doussau A, Poirier N, Simard MN, Gallagher A. Language brain responses and neurodevelopmental outcome in preschoolers with congenital heart disease: A fNIRS study.Neuropsychologia. 2024;196:108843.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 7][Reference Citation Analysis (0)]
Sood E, Newburger JW, Anixt JS, Cassidy AR, Jackson JL, Jonas RA, Lisanti AJ, Lopez KN, Peyvandi S, Marino BS; American Heart Association Council on Lifelong Congenital Heart Disease and Heart Health in the Young and the Council on Cardiovascular and Stroke Nursing. Neurodevelopmental Outcomes for Individuals With Congenital Heart Disease: Updates in Neuroprotection, Risk-Stratification, Evaluation, and Management: A Scientific Statement From the American Heart Association.Circulation. 2024;149:e997-e1022.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 127][Reference Citation Analysis (0)]
Abou Al Fotouh MN, Alghobashy AA, Abou Al Magd YES, Raafat N, Hassan HM. Evaluation of N-Terminal Pro Brain Natriuretic Peptide as a biomarker for clinical severity of heart failure in pediatric population.Afro-Egypt J Infect Endem Dis. 2017;7:37-46.
[PubMed] [DOI] [Full Text]
Shaarawy S, Morsy SM, Khalifa NA, Ahmed AI. Comparative Study Between Modified Ross Score and Pediatric Heart Failure Index using pro-BNP in Quantifying Severity of Heart Failure in Pediatrics.Zagazig Univ Med J. 2023;29:17-24.
[PubMed] [DOI] [Full Text]
Zhou XJ, Zhang X, Zhang J, Zhou L, Zhou TT, Zhang JW. Diagnostic value of growth differentiation factor-15 and β2-microglobulin in children with congenital heart disease combined with chronic heart failure and its relationship with cardiac function.Eur Rev Med Pharmacol Sci. 2020;24:8096-8103.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 5][Reference Citation Analysis (0)]
Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor JW, Mussatto KA, Uzark K, Goldberg CS, Johnson WH Jr, Li J, Smith SE, Bellinger DC, Mahle WT; American Heart Association Congenital Heart Defects Committee, Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, and Stroke Council. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association.Circulation. 2012;126:1143-1172.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1415][Cited by in RCA: 1206][Article Influence: 86.1][Reference Citation Analysis (0)]
