Abstract
Introduction
The omic approach can help identify a signature that can be potentially used as biomarkers in babies with congenital diaphragmatic hernia (CDH).
Objectives
To find a specific microRNA (miR) and metabolic fingerprint of the tracheal aspirates (TA) of CDH patients. We conducted a genetic analysis from blood samples.
Methods
TA samples collected in the first 48 h of life in patients with CDH, compared with age-matched controls. Metabolomics done by a mass spectroscopy-based assay. Genomics done using chromosomal microarray analysis.
Results
CDH (n = 17) and 16 control neonates enrolled. miR-16, miR-17, miR-18, miR-19b, and miR-20a had an increased expression, while miR-19a had a twofold decreased expression in CDH patients, compared with age-matched control patients. Specific metabolites separated neonates with CDH from controls. A genetic mutation found in a small subset of patients.
Conclusions
Specific patterns of metabolites and miR expression can be discerned in TA samples in infants with CDH.
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References
Langham MR Jr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia. Epidemiology and outcome. Clin Perinatol. 1996;23:671–88.
Desai AA, Ostlie DJ, Juang D. Optimal timing of congenital diaphragmatic hernia repair in infants on extracorporeal membrane oxygenation. Semin Pediatr Surg. 2015;24:17–9.
Hedrick HL. Management of prenatally diagnosed congenital diaphragmatic hernia. Semin Pediatr Surg. 2013;22:37–43.
Jani JC, Nicolaides KH, Gratacos E, Valencia CM, Done E, Martinez JM, et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2009;34:304–10.
Shue EH, Miniati D, Lee H. Advances in prenatal diagnosis and treatment of congenital diaphragmatic hernia. Clin Perinatol. 2012;39:289–300.
Chiu PP, Ijsselstijn H. Morbidity and long-term follow-up in CDH patients. Eur J Pediatr Surg. 2012;22:384–92.
Pennaforte T, Rakza T, Fily A, Mur S, Diouta L, Sfeir R. et al. [The long-term follow-up of patients with a congenita diaphragmatic hernia: review of the literature]. Arch Pediatr. 2013;20 (Suppl 1):S11–8.
Spoel M, van den Hout L, Gischler SJ, Hop WC, Reiss I, Tibboel D, et al. Prospective longitudinal evaluation of lung function during the first year of life after repair of congenital diaphragmatic hernia. Pediatr Crit Care Med. 2012;13:e133–9.
Herrera-Rivero M, Zhang R, Heilmann-Heimbach S, Mueller A, Bagci S, Dresbach T, et al. Circulating microRNAs are associated with pulmonary hypertension and development of chronic lung disease in congenital diaphragmatic hernia. Sci Rep. 2018;8:10735.
Pelizzo G, Ballico M, Mimmi MC, Peiro JL, Marotta M, Federico C, et al. Metabolomic profile of amniotic fluid to evaluate lung maturity: the diaphragmatic hernia lamb model. Multidiscip Respir Med. 2014;9:54.
Iorio MV, Croce CM. Causes and consequences of microRNA dysregulation. Cancer J. 2012;18:215–22.
Griffiths WJ, Koal T, Wang Y, Kohl M, Enot DP, Deigner HP. Targeted metabolomics for biomarker discovery. Angew Chem Int Ed Engl. 2010;49:5426–45.
Bienertova-Vasku J, Novak J, Vasku A. MicroRNAs in pulmonary arterial hypertension: pathogenesis, diagnosis and treatment. J Am Soc Hypertens. 2015;9:221–34.
Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med. 2012;185:409–19.
Pereira-Terra P, Deprest JA, Kholdebarin R, Khoshgoo N, DeKoninck P, Munck AA, et al. Unique tracheal fluid MicroRNA signature predicts response to FETO in patients with congenital diaphragmatic hernia. Ann Surg. 2015;262:1130–40.
de Blic J, Midulla F, Barbato A, Clement A, Dab I, Eber E, et al. Bronchoalveolar lavage in children. ERS Task Force on bronchoalveolar lavage in children. European Respiratory Society. Eur Respir J. 2000;15:217–31.
Piersigilli F, Lam TT, Vernocchi P, Quagliariello A, Putignani L, Aghai ZH, et al. Identification of new biomarkers of bronchopulmonary dysplasia using metabolomics. Metabolomics. 2019;15:20.
Team RC. A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2017. https://www.R-projectorg/.
Culhane AC, Thioulouse J, Perriere G, Higgins DG. MADE4: an R package for multivariate analysis of gene expression data. Bioinformatics. 2005;21:2789–90.
Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 2013;20:1603–14.
Negi V, Chan SY. Discerning functional hierarchies of microRNAs in pulmonary hypertension. JCI Insight. 2017;2:e91327.
Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, et al. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet. 1995;11:415–21.
Quinn TM, Sylvester KG, Kitano Y, Kitano Y, Liechty KW, Jarrett BP, et al. TGF-beta2 is increased after fetal tracheal occlusion. J Pediatr Surg. 1999;34:701–4. discussion 704-5.
Oue T, Shima H, Taira Y, Puri P. Administration of antenatal glucocorticoids upregulates peptide growth factor gene expression in nitrofen-induced congenital diaphragmatic hernia in rats. J Pediatr Surg. 2000;35:109–12.
Chen H, Zhuang F, Liu YH, Xu B, Del Moral P, Deng W, et al. TGF-beta receptor II in epithelia versus mesenchyme plays distinct roles in the developing lung. Eur Respir J. 2008;32:285–95.
McDevitt TM, Gonzales LW, Savani RC, Ballard PL. Role of endogenous TGF-beta in glucocorticoid-induced lung type II cell differentiation. Am J Physiol Lung Cell Mol Physiol. 2007;292:L249–57.
Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, et al. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension. Circulation. 2017;135:460–75.
Zhao Y, Peng J, Lu C, Hsin M, Mura M, Wu L, et al. Metabolomic heterogeneity of pulmonary arterial hypertension. PLoS ONE. 2014;9:e88727.
Lewis GD, Ngo D, Hemnes AR, Farrell L, Domos C, Pappagianopoulos PP, et al. Metabolic profiling of right ventricular-pulmonary vascular function reveals circulating biomarkers of pulmonary hypertension. J Am Coll Cardiol. 2016;67:174–89.
Shao Z, Wang Z, Shrestha K, Thakur A, Borowski AG, Sweet W, et al. Pulmonary hypertension associated with advanced systolic heart failure: dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1. J Am Coll Cardiol. 2012;59:1150–8.
Zhao YD, Chu L, Lin K, Granton E, Yin L, Peng J, et al. A biochemical approach to understand the pathogenesis of advanced pulmonary arterial hypertension: metabolomic profiles of arginine, sphingosine-1-phosphate, and heme of human lung. PLoS ONE. 2015;10:e0134958.
Cheah FC, Darlow BA, Winterbourn CC. Association of hydrogen peroxide in exhaled breath condensates from infants with respiratory distress syndrome with the development of chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2006;91:F155.
Rosso MI, Roark S, Taylor E, Ping X, Ward JM, Roche K, et al. Exhaled breath condensate in intubated neonates–a window into the lung's glutathione status. Respir Res. 2014;115;1.
Kononikhin AS, Starodubtseva NL, Chagovets VV, Ryndin AY, Burov AA, Popov IA, et al. Exhaled breath condensate analysis from intubated newborns by nano-HPLC coupled to high resolution MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2017;1047:97–105.
Pober BR. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH. Am J Med Genet C Semin Med Genet. 2007;145C:158–71.
Holder AM, Klaassens M, Tibboel D, de Klein A, lee b, Scott DA. Genetic factors in congenital diaphragmatic hernia. Am J Hum Genet. 2007;80:825–45.
Beck TF, Campeau PM, Jhangiani SN, Gambin T, Li AH, Abo-zahrah R, et al. FBN1 contributing to familial congenital diaphragmatic hernia. Am J Med Genet A. 2015;167A:831–6.
Beck TF, Veenma D, Shchelochkov OA, Yu Z, Kim BJ, Zaveri HP, et al. Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice. Hum Mol Genet. 2013;22:1026–38.
Yu L, Wynn J, Ma L, Guha S, Mychaliska GB, Crombleholme TM, et al. De novo copy number variants are associated with congenital diaphragmatic hernia. J Med Genet. 2012;49:650–9.
Longoni M, High FA, Qi H, Joy MP, Hila R, Coletti CM, et al. Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia. Hum Genet. 2017;136:679–91.
Qi H, Yu L, Zhou X, Wynn J, Zhao H, Guo Y, et al. De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet. 2018;14:e1007822.
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Piersigilli, F., Syed, M., Lam, T.T. et al. An omic approach to congenital diaphragmatic hernia: a pilot study of genomic, microRNA, and metabolomic profiling. J Perinatol 40, 952–961 (2020). https://doi.org/10.1038/s41372-020-0623-3
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DOI: https://doi.org/10.1038/s41372-020-0623-3