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. 2023 Feb 13;10(2):78.
doi: 10.3390/jcdd10020078.

Maternal Serum tRNA-Derived Fragments (tRFs) as Potential Candidates for Diagnosis of Fetal Congenital Heart Disease

Enkang Lu  1   2 , Lijun Wu  3 , Bin Chen  1 , Shipeng Xu  4 , Ziyi Fu  2 , Yun Wu  3 , Yanhu Wu  1 , Haitao Gu  1
Affiliations

Maternal Serum tRNA-Derived Fragments (tRFs) as Potential Candidates for Diagnosis of Fetal Congenital Heart Disease

Enkang Lu et al. J Cardiovasc Dev Dis. .

Abstract

Background: Congenital heart disease (CHD) is one of the most predominant birth defects that causes infant death worldwide. The timely and successful surgical treatment of CHD on newborns after delivery requires accurate detection and reliable diagnosis during pregnancy. However, there are no biomarkers that can serve as an early diagnostic factor for CHD patients. tRNA-derived fragments (tRFs) have been reported to play an important role in the occurrence and progression of numerous diseases, but their roles in CHD remains unknown.

Methods: High-throughput sequencing was performed on the peripheral blood of pregnant women with an abnormal fetal heart and a normal fetal heart, and 728 differentially expressed tRFs/tiRNAs were identified, among which the top 18 tRFs/tiRNAs were selected as predictive biomarkers of CHD. Then, a quantitative reverse transcriptase polymerase chain reaction verified the expression of tRFs/tiRNAs in more clinical samples, and the correlation between tRFs/tiRNAs abnormalities and CHD was analyzed.

Results: tRF-58:74-Gly-GCC-1 and tiRNA-1:35-Leu-CAG-1-M2 may be promising biomarkers. Through further bioinformatics analysis, we predicted that TRF-58:744-GLy-GCC-1 could induce CHD by influencing biological metabolic processes.

Conclusions: Our results provide a theoretical basis for the abnormally expressed tRF-58:74-Gly-GCC-1 in maternal peripheral blood as a new potential biomarker for the accurate diagnosis of CHD during pregnancy.

Keywords: biomarker; cardiac development; congenital heart disease; tRFs/tiRNAs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Correlation of samples and catalogue of tRFs/tiRNAs expressed in pregnant women with abnormal fetal heart and normal fetal hearts. (a) Coefficient of correlation between samples. (b) Principal component analysis (PCA). (c,d) The read length. (e,f) Stack diagram of all subtypes of each tRF/tiRNA, clustered by anti-codon of tRNA. The colored bars represent the number of tRFs/tiRNAs per subtype.
Figure 2
Figure 2
Differential expression of tRFs/tiRNAs between pregnant women with abnormal fetal heart and normal fetal hearts. (a) Heatmaps of aberrantly expressed tRFs/tiRNAs in pregnant women with fetal heart defects and normal fetal hearts. (b) Volcanic diagrams of aberrantly expressed tRFs/tiRNAs in pregnant women with fetal heart defects and normal fetal hearts, 66 tRFs/tiRNAs were reported to be dysregulated in group disease compared with group control, of which 28 were up-regulated and 38 were down-regulated. (c) Out of a total of 728 differentially regulated tRFs/tiRNAs detected, 88 could be found in tRFdb, and the rest were unknown. (d) 61 tRFs/tiRNAs specifically expressed in group disease and 130 tRFs/tiRNAs specifically expressed in group control. (e,f) The percentage of expression of each isoform of tRFs/tiRNAs in the two groups of samples.
Figure 3
Figure 3
Verification of 2 regulatory anomalies tRFs/tiRNAs in pregnant women with abnormal fetal heart and normal fetal hearts. (a,b) The position of each tRFs/tiRNAs on the shamrock secondary structure derived from tRNA is shown. tRFs/tiRNAs expression in serum of pregnant women with abnormal fetal heart and normal fetal hearts was analyzed by qRT-PCR. All data were analyzed by Student’s t test. The asterisk indicates how significant the difference between the groups is (* p < 0.05, *** p < 0.001, ns, non-significant). (c) Verification of 18 tRFs/tiRNAs (12 Disease vs. 12 Control). (d) Verification of tRF-58:74-Gly-GCC-1 (35 Disease vs. 48 Control). (e) Verification of tiRNA-1:35-Leu-CAG-1 M2 (35 Disease vs. 48 Control). (f,g) Verification of tRF-58:74-Gly-GCC-1 and tiRNA-1:35-Leu-CAG-1 M2 for certain CHD defects.
Figure 4
Figure 4
ROC curve, GO and KEGG pathway analysis of specific tRFs/tiRNAs. (a,b) The vertical axis is sensitivity, the horizontal axis is 1-specificity. AUC is a parameter used to measure the value of tRFs/tiRNAs in the diagnosis of fetal CHD. (c–f) GO and KEGG pathway analysis of tRF-58:74-Gly-GCC-1 and tiRNA-1:35-Leu-CAG-1-M2.
Figure 5
Figure 5
Protein–protein interaction networks of tRF-58:74-Gly-GCC-1 and tiRNA-1:35-Leu-CAG-1-M2. (a) The protein–protein interaction network of corresponding target genes oftRF-58:74-Gly-GCC-1 and (b) tiRNA-1:35-Leu-CAG-1-M2.
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