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Analysis of Biomarkers for Congenital Heart Disease Based on Maternal Amniotic Fluid Metabolomics.

ABSTRACT: Congenital heart disease (CHD) is the most common birth defect. The prenatal diagnosis of fetal CHD is completely dependent on ultrasound testing, but only ~40% of CHD can be detected. The purpose of this study is to find good biomarkers in amniotic fluid (AF) to detect CHD in the second trimester, so as to better manage this group of people and reduce the harm of CHD to the fetus. Metabolites analysis were performed in two separate sets. The discovery set consisted of 18 CHD fetal maternal AF samples and 35 control samples, and the validation set consisted of 53 CHD fetal maternal AF samples and 114 control samples. Untargeted metabolite profiles were analyzed by gas chromatography/time-of-flight-mass spectrometry (GC-TOF/MS). Orthogonal partial least square discrimination analysis (OPLS-DA) demonstrated that CHD and control samples had significantly different metabolic profiles. Two metabolites, uric acid and proline, were significantly elevated in CHD and verified in two data sets. Uric acid was associated with CHD [odds ratio (OR): 7.69 (95% CI: 1.18-50.13) in the discovery set and 3.24 (95% CI:1.62-6.48) in the validation set]. Additionally, uric acid showed moderate predictive power; the area under curve (AUC) was 0.890 in the discovery set and 0.741 in the validation set. The sensitivity and specificity of uric acid to detect CHD was, respectively, 94.4 and 74.3% in the discovery set and 67.9 and 71.9% in the validation set. The identification of uric acid as a biomarker for CHD has the potential to stimulate research on the pathological mechanism of CHD and the development of a diagnostic test for clinical applications.

SUBMITTER: Li Y

PROVIDER: S-EPMC8215886 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThere has been significant research on the genetic and environmental factors of congenital heart defects (CHDs), but few causes of teratogenicity, especially teratogenic mechanisms, can be clearly identified. Metabolomics has a potential advantage in researching the relationship between external factors and CHD.ObjectiveTo find and identify the urinary potential biomarkers of pregnancy (including in the second and third trimesters) for fetuses with CHD based on modified gas chromatograph-mass spectrometer (GC-MS), which could reveal the possibility of high-risk factors for CHD and lay the foundation for early intervention, treatment, and prevention.MethodsUsing a case-control design, we measured the urinary potential biomarkers of maternal urine metabolomics based on GC-MS in a population-based sample of women whose infants were diagnosed with CHD (70 case subjects) or were healthy (70 control subjects). SIMCA-P 13.0 software, principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), Wilcoxon-Mann-Whitney test, and logistics regression were used to find significant potential biomarkers.ResultThe 3D score graph of the OPLS-DA showed that the CHD and control groups were fully separated. The fitting parameters were R2x=0.78 and R2y=0.69, and the forecast rate was Q2=0.61, indicating a high forecast ability. According to the ranking of VIPs from the OPLS-DA models, we found 34 potential metabolic markers with a VIP > 1, and after two pairwise rank sum tests, we found 20 significant potential biomarkers, which were further used in multifactor logistic regressions. Significant substances, including 4-hydroxybenzeneacetic acid (OR=4.74, 95% CI: 1.06-21.06), 5-trimethylsilyloxy-n-valeric acid (OR=15.78, 95% CI: 2.33-106.67), propanedioic acid (OR=5.37, 95% CI: 1.87-15.45), hydracrylic acid (OR=6.23, 95% CI: 1.07-36.21), and uric acid (OR=5.23, 95% CI: 1.23-22.32), were associated with CHD.ConclusionThe major potential biomarkers in maternal urine associated with CHD were 4-hydroxybenzeneacetic acid, 5-trimethylsilyloxy-n-valeric acid, propanedioic acid, hydracrylic acid, and uric acid, respectively. These results indicated that the short chain fatty acids (SCFAs) and aromatic amino acid metabolism may be relevant with CHD.

Project description:Background: Congenital cytomegalovirus (cCMV) is a common intrauterine infection, leading to neurodevelopmental disabilities. Early prognostic assessment of the severity of cCMV has remained an ongoing challenge. We aimed to identify amniotic fluid biomarkers of the severity of cCMV-related fetal brain injury. Methods: Global proteome analysis was performed in mid-gestation amniotic fluid samples, comparing fetuses with severe cCMV to asymptomatic CMV-infected fetuses (the discovery cohort). The levels of selected differentially-excreted proteins were further determined by specific immunoassays, and evaluated in an independent validation cohort, including clinically-blinded amniotic fluid of CMV-infected fetuses from unrelated centers. Findings: Proteome analysis identified 29 amniotic fluid proteins with distinct abundance in fetuses with severe-, compared to asymptomatic, cCMV. Pathway analysis of the differentially-excreted proteins revealed enriched pathways of inflammatory response, cellular compromise, immunological disease, organismal injury, and neurological disease, underlining a link between excessive inflammation at the maternal-fetal interface and the development of cCMV-related fetal brain damage. Importantly, the levels of two of these proteins, chemerin and galectin-3-binding protein (Gal-3BP), selected for validation, demonstrated 88.2% sensitivity (each), 100-96.2% specificity, 100-93.8% positive predictive value, and 92.9-92.6% negative predictive value, with 0.98-0.97 area under the curve (for chemerin - Gal-3BP, respectively) in differentiating 17 fetuses with severe cCMV from 26 asymptomatic CMV-infected fetuses. Interpretation: These results identify the immunomodulatory proteins chemerin and Gal-3BP as new highly predictive amniotic fluid biomarkers of cCMV severity, which could guide early prognostic stratification and potential personalized treatment of cCMV-infected fetuses. Funding: Israel Science Foundation; Research Fund of the Hadassah Medical Organization

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Analysis of Biomarkers for Congenital Heart Disease Based on Maternal Amniotic Fluid Metabolomics.

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