Identification and Analysis of Inflammation-related Biomarkers in Tetralogy of Fallot

Overview

Journal Transl Pediatr

Publisher AME Publishing Company

Specialty Pediatrics

Date 2024 Aug 15

PMID 39144431

Authors

Junzhe Du

Huaipu Liu

Pengcheng Wang

Wenzhi Wu

Fengnan Zheng

Yuanxiang Wang

Baoying Meng

Affiliations

Soon will be listed here.

Abstract

Background: Studies have revealed that inflammatory response is relevant to the tetralogy of Fallot (TOF). However, there are no studies to systematically explore the role of the inflammation-related genes (IRGs) in TOF. Therefore, based on bioinformatics, we explored the biomarkers related to inflammation in TOF, laying a theoretical foundation for its in-depth study.

Methods: TOF-related datasets (GSE36761 and GSE35776) were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between TOF and control groups were identified in GSE36761. And DEGs between TOF and control groups were intersected with IRGs to obtain differentially expressed IRGs (DE-IRGs). Afterwards, the least absolute shrinkage and selection operator (LASSO) and random forest (RF) were utilized to identify the biomarkers. Next, immune analysis was carried out. The transcription factor (TF)-mRNA, lncRNA-miRNA-mRNA, and miRNA-single nucleotide polymorphism (SNP)-mRNA networks were created. Finally, the potential drugs targeting the biomarkers were predicted.

Results: There were 971 DEGs between TOF and control groups, and 29 DE-IRGs were gained through the intersection between DEGs and IRGs. Next, a total of five biomarkers (MARCO, CXCL6, F3, SLC7A2, and SLC7A1) were acquired via two machine learning algorithms. Infiltrating abundance of 18 immune cells was significantly different between TOF and control groups, such as activated B cells, neutrophil, CD56dim natural killer cells, etc. The TF-mRNA network contained 4 mRNAs, 31 TFs, and 33 edges, for instance, ELF1-CXCL6, CBX8-SLC7A2, ZNF423-SLC7A1, ZNF71-F3. The lncRNA-miRNA-mRNA network was created, containing 4 mRNAs, 4 miRNAs, and 228 lncRNAs. Afterwards, nine SNPs locations were identified in the miRNA-SNP-mRNA network. A total of 21 drugs were predicted, such as ornithine, lysine, arginine, etc.

Conclusions: Our findings detected five inflammation-related biomarkers (MARCO, CXCL6, F3, SLC7A2, and SLC7A1) for TOF, providing a scientific reference for further studies of TOF.

Citing Articles

Radiomics with structural magnetic resonance imaging, surface morphometry features, neurology scales, and clinical metrics to evaluate the neurodevelopment of preschool children with corrected tetralogy of Fallot.

Yang F, Zhong J, Liu P, Yu W, Liu Y, Zhu M Transl Pediatr. 2024; 13(9):1571-1587.

PMID: 39399711 PMC: 11467234. DOI: 10.21037/tp-24-219.

References

Bittel D, Zhou X, Kibiryeva N, Fiedler S, OBrien Jr J, Marshall J . Ultra high-resolution gene centric genomic structural analysis of a non-syndromic congenital heart defect, Tetralogy of Fallot. PLoS One. 2014; 9(1):e87472. PMC: 3909147. DOI: 10.1371/journal.pone.0087472. View

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

Gong J, Liu C, Liu W, Wu Y, Ma Z, Chen H . An update of miRNASNP database for better SNP selection by GWAS data, miRNA expression and online tools. Database (Oxford). 2015; 2015:bav029. PMC: 4397995. DOI: 10.1093/database/bav029. View

Manuel V, Miana L, Guerreiro G, Turquetto A, Medeiros Santos R, Fernandes N . Preoperative Neutrophil-Lymphocyte Ratio Can Predict Outcomes for Patients Undergoing Tetralogy of Fallot Repair. Braz J Cardiovasc Surg. 2021; 36(5):607-613. PMC: 8597611. DOI: 10.21470/1678-9741-2020-0408. View

Eltzschig H, Carmeliet P . Hypoxia and inflammation. N Engl J Med. 2011; 364(7):656-65. PMC: 3930928. DOI: 10.1056/NEJMra0910283. View

McElhinney D, Driscoll D, Levin E, Jawad A, Emanuel B, Goldmuntz E . Chromosome 22q11 deletion in patients with ventricular septal defect: frequency and associated cardiovascular anomalies. Pediatrics. 2003; 112(6 Pt 1):e472. DOI: 10.1542/peds.112.6.e472. View

Sheng W, Qian Y, Wang H, Ma X, Zhang P, Diao L . DNA methylation status of NKX2-5, GATA4 and HAND1 in patients with tetralogy of fallot. BMC Med Genomics. 2013; 6:46. PMC: 3819647. DOI: 10.1186/1755-8794-6-46. View

Kan Z, Yan W, Wang N, Fang Y, Gao H, Song Y . Identification of circRNA-miRNA-mRNA Regulatory Network and Crucial Signaling Pathway Axis Involved in Tetralogy of Fallot. Front Genet. 2022; 13:917454. PMC: 9300927. DOI: 10.3389/fgene.2022.917454. View

Wienecke L, Cohen S, Bauersachs J, Mebazaa A, Chousterman B . Immunity and inflammation: the neglected key players in congenital heart disease?. Heart Fail Rev. 2021; 27(5):1957-1971. PMC: 8636791. DOI: 10.1007/s10741-021-10187-6. View

10.

Hamada H, Terai M, Kimura H, Hirano K, Oana S, Niimi H . Increased expression of mast cell chymase in the lungs of patients with congenital heart disease associated with early pulmonary vascular disease. Am J Respir Crit Care Med. 1999; 160(4):1303-8. DOI: 10.1164/ajrccm.160.4.9810058. View

11.

Waehre A, Vistnes M, Sjaastad I, Nygard S, Husberg C, Lunde I . Chemokines regulate small leucine-rich proteoglycans in the extracellular matrix of the pressure-overloaded right ventricle. J Appl Physiol (1985). 2012; 112(8):1372-82. DOI: 10.1152/japplphysiol.01350.2011. View

12.

Yu Y, Ge X, Wang L, Wang X, Xu L . Abnormalities of hsa-mir-16 and hsa-mir-124 Affect Mitochondrial Function and Fatty Acid Metabolism in Tetralogy of Fallot. Comb Chem High Throughput Screen. 2022; 26(2):373-382. DOI: 10.2174/1386207325666220421104617. View

13.

Grunert M, Dorn C, Schueler M, Dunkel I, Schlesinger J, Mebus S . Rare and private variations in neural crest, apoptosis and sarcomere genes define the polygenic background of isolated Tetralogy of Fallot. Hum Mol Genet. 2014; 23(12):3115-28. DOI: 10.1093/hmg/ddu021. View

14.

Girard T, Antunes L, Zhang N, Amrute J, Subramanian R, Eldem I . Peripheral blood mononuclear cell tissue factor (F3 gene) transcript levels and circulating extracellular vesicles are elevated in severe coronavirus 2019 (COVID-19) disease. J Thromb Haemost. 2023; 21(3):629-638. PMC: 9773443. DOI: 10.1016/j.jtha.2022.11.033. View

15.

Liang D, Xu X, Deng F, Feng J, Zhang H, Liu Y . miRNA-940 reduction contributes to human Tetralogy of Fallot development. J Cell Mol Med. 2014; 18(9):1830-9. PMC: 4196658. DOI: 10.1111/jcmm.12309. View

16.

Mittal P, Romero R, Kusanovic J, Edwin S, Gotsch F, Mazaki-Tovi S . CXCL6 (granulocyte chemotactic protein-2): a novel chemokine involved in the innate immune response of the amniotic cavity. Am J Reprod Immunol. 2008; 60(3):246-57. PMC: 2577773. DOI: 10.1111/j.1600-0897.2008.00620.x. View

17.

Zhang X, Gao Y, Zhang X, Zhang X, Xiang Y, Fu Q . Is a Hub lncRNA ceRNA in Hearts With Tetralogy of Fallot Which Regulates Congenital Heart Disease Genes Transcriptionally and Epigenetically. Front Cell Dev Biol. 2021; 9:630634. PMC: 8144506. DOI: 10.3389/fcell.2021.630634. View

18.

Dong Q, Zhang S, Zhang H, Sun J, Lu J, Wang G . MARCO is a potential prognostic and immunotherapy biomarker. Int Immunopharmacol. 2023; 116:109783. DOI: 10.1016/j.intimp.2023.109783. View

19.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

20.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View