Download PDF
Thorac Cardiovasc Surg 2018; 66(01): 116-124
DOI: 10.1055/s-0037-1604083
Original Basic Science
Georg Thieme Verlag KG Stuttgart · New York

Characterization of micro-RNA Profile in the Blood of Patients with Marfan's Syndrome

Masood Abu-Halima
1   Department of Human Genetics, Saarland University, Homburg/Saar, Germany
,
Nicole Ludwig
1   Department of Human Genetics, Saarland University, Homburg/Saar, Germany
,
Tanja Rädle-Hurst
2   Department of Pediatric Cardiology, Saarland University Medical Center, Homburg/Saar, Germany
,
Andreas Keller
3   Chair for Clinical Bioinformatics, Saarland University, Saarbruecken, Germany
,
Lars Motsch
2   Department of Pediatric Cardiology, Saarland University Medical Center, Homburg/Saar, Germany
,
Ina Marsollek
2   Department of Pediatric Cardiology, Saarland University Medical Center, Homburg/Saar, Germany
,
Mohammed Abd El Rahman
2   Department of Pediatric Cardiology, Saarland University Medical Center, Homburg/Saar, Germany
,
Hashim Abdul-Khaliq   *
2   Department of Pediatric Cardiology, Saarland University Medical Center, Homburg/Saar, Germany
,
Eckart Meese   *
1   Department of Human Genetics, Saarland University, Homburg/Saar, Germany
› Author Affiliations
Further Information

Publication History

02 March 2017

29 May 2017

Publication Date:
05 July 2017 (online)

    Permissions and Reprints All articles of this category

Abstract

Background Marfan's syndrome (MFS) is an autosomal dominant inheritance disorder with a 1/5,000 live-birth prevalence. It is characterized by a wide range of clinical manifestations with more than 3,000 mutations identified in the FBN1 gene. In this study, we aimed to determine if specific patterns of circulating micro-RNAs (miRNAs) are associated with MFS-associated with cardiovascular diseases.

Methods Microarray-based miRNA profiling was performed on blood samples of 12 MFS patients, and 12 healthy volunteers (HVs) controls and the differences in miRNA abundance between the two groups were validated using independent cohorts of 22 MFS and of 22 HV controls by real-time quantitative polymerase chain reaction (RT-qPCR). Enrichment analyses of altered miRNA abundance were predicted using bioinformatics tools.

Results Altered miRNA abundance levels were determined between MFS (n = 34) and HVs (n = 34). In a screening phase, we analyzed 12 patients with MFS and 12 HVs by miRNA microarray. We found 198 miRNAs that were significantly altered in MFS patients as compared with HVs, including 16 miRNAs with a more than 1.5-fold change. Out of these 16 miRNAs, 10 showed a decreased abundance and 6 showed an increased abundance. In the validation phase, we analyzed independent cohorts of 22 MFS and of 22 HV controls by RT-qPCR. We confirmed the direction of abundance changes and the significance of different abundances between MFS patients and HVs for four miRNAs, namely, miR-362–5p, miR-339–3p, miR-340–5p, and miR-210–3p. Only the miR-150–5p showed a significant correlation with mitral valve prolapse (p = 0.010). The predicted targets for the validated miRNAs were associated with signal transduction, tissue remodeling, and cellular interaction pathways.

Conclusion The altered abundance level of different miRNAs in whole blood of MFS patients lays the ground to the development of novel diagnostic approaches with altered miRNAs levels associated with MFS with manifestations associated with cardiovascular diseases.

Keywords

Micro-RNA - Marfan syndrome - fibrillin

Authors' Contributions

• M.A. performed experimental work, particularly the miRNA array experiment, RT-qPCR validation, and wrote the article.


• N.L. helped in RT-qPCR validation experiments and edited the article.


• L.M. helped in experimental work and samples collection.


• I.M. isolated RNA and assessed the quality and quantity of RNA.


• G.G. helped in patients' diagnosis and samples collection.


• T.R.H. helped in patients' diagnosis and samples collection.


• M.A.R. helped in patients' diagnosis and samples collection.


• A.K. performed bioinformatics analysis.


• E.M. designed the study, coordinated the molecular biology experiment, and wrote/edited the article.


• H.A.K. designed the study, diagnosed patients, collected the samples, and edited the article.


* Both the authors contributed equally to this work.


Supplementary Material

 

  • References

  • 1 Faivre L, Collod-Beroud G, Child A. , et al. Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands. J Med Genet 2008; 45 (06) 384-390
    CrossrefPubMedGoogle Scholar
  • 2 Collod-Béroud G, Boileau C. Marfan syndrome in the third Millennium. Eur J Hum Genet 2002; 10 (11) 673-681
    CrossrefPubMedGoogle Scholar
  • 3 Jondeau G, Michel JB, Boileau C. The translational science of Marfan syndrome. Heart 2011; 97 (15) 1206-1214
    CrossrefPubMedGoogle Scholar
  • 4 Judge DP, Dietz HC. Marfan's syndrome. Lancet 2005; 366 (9501): 1965-1976
    CrossrefPubMedGoogle Scholar
  • 5 Ramachandra CJ, Mehta A, Guo KW, Wong P, Tan JL, Shim W. Molecular pathogenesis of Marfan syndrome. Int J Cardiol 2015; 187: 585-591
    CrossrefPubMedGoogle Scholar
  • 6 Stheneur C, Collod-Béroud G, Faivre L. , et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet 2009; 17 (09) 1121-1128
    CrossrefPubMedGoogle Scholar
  • 7 von Kodolitsch Y, De Backer J, Schüler H. , et al. Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome. Appl Clin Genet 2015; 8: 137-155
    PubMedGoogle Scholar
  • 8 Keane MG, Pyeritz RE. Medical management of Marfan syndrome. Circulation 2008; 117 (21) 2802-2813
    CrossrefPubMedGoogle Scholar
  • 9 Abd El Rahman M, Haase D, Rentzsch A. , et al. Left ventricular systolic dysfunction in asymptomatic Marfan syndrome patients is related to the severity of gene mutation: insights from the novel three dimensional speckle tracking echocardiography. PLoS One 2015; 10 (04) e0124112
    CrossrefPubMedGoogle Scholar
  • 10 Collod-Béroud G, Le Bourdelles S, Ades L. , et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 2003; 22 (03) 199-208
    CrossrefPubMedGoogle Scholar
  • 11 Faivre L, Collod-Beroud G, Loeys BL. , et al. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007; 81 (03) 454-466
    CrossrefPubMedGoogle Scholar
  • 12 Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 2012; 13 (04) 271-282
    CrossrefPubMedGoogle Scholar
  • 13 Romaine SP, Tomaszewski M, Condorelli G, Samani NJ. MicroRNAs in cardiovascular disease: an introduction for clinicians. Heart 2015; 101 (12) 921-928
    CrossrefPubMedGoogle Scholar
  • 14 Merk DR, Chin JT, Dake BA. , et al. miR-29b participates in early aneurysm development in Marfan syndrome. Circ Res 2012; 110 (02) 312-324
    CrossrefPubMedGoogle Scholar
  • 15 Abu-Halima M, Ludwig N, Hart M. , et al. Altered micro-ribonucleic acid expression profiles of extracellular microvesicles in the seminal plasma of patients with oligoasthenozoospermia. Fertil Steril 2016; 106 (05) 1061-1069.e3
    CrossrefPubMedGoogle Scholar
  • 16 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25 (04) 402-408
    CrossrefPubMedGoogle Scholar
  • 17 Busch A, Busch M, Scholz CJ. , et al. Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology. Int J Mol Sci 2016; 17 (01) 17
    PubMedGoogle Scholar
  • 18 Chen F, Zhao X, Peng J, Bo L, Fan B, Ma D. Integrated microRNA-mRNA analysis of coronary artery disease. Mol Biol Rep 2014; 41 (08) 5505-5511
    CrossrefPubMedGoogle Scholar
  • 19 Zeng L, Liu J, Wang Y. , et al. MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front Biosci (Elite Ed) 2011; 3: 1265-1272
    PubMedGoogle Scholar
  • 20 Zhang R, Lan C, Pei H, Duan G, Huang L, Li L. Expression of circulating miR-486 and miR-150 in patients with acute myocardial infarction. BMC Cardiovasc Disord 2015; 15: 51
    CrossrefPubMedGoogle Scholar
  • 21 Al-Kafaji G, Al-Mahroos G, Abdulla Al-Muhtaresh H, Sabry MA, Abdul Razzak R, Salem AH. Circulating endothelium-enriched microRNA-126 as a potential biomarker for coronary artery disease in type 2 diabetes mellitus patients. Biomarkers 2017; 22 (3-4): 268-278
    CrossrefPubMedGoogle Scholar
  • 22 Zampetaki A, Willeit P, Tilling L. , et al. Prospective study on circulating MicroRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012; 60 (04) 290-299
    CrossrefPubMedGoogle Scholar
  • 23 Bostjancic E, Zidar N, Glavac D. MicroRNA microarray expression profiling in human myocardial infarction. Dis Markers 2009; 27 (06) 255-268
    CrossrefPubMedGoogle Scholar
  • 24 Fichtlscherer S, Zeiher AM, Dimmeler S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases?. Arterioscler Thromb Vasc Biol 2011; 31 (11) 2383-2390
    CrossrefPubMedGoogle Scholar
  • 25 Zhou J, Gao J, Zhang X. , et al. microRNA-340-5p Functions Downstream of Cardiotrophin-1 to Regulate Cardiac Eccentric Hypertrophy and Heart Failure via Target Gene Dystrophin. Int Heart J 2015; 56 (04) 454-458
    CrossrefPubMedGoogle Scholar
  • 26 Zhu X, Wang H, Liu F. , et al. Identification of micro-RNA networks in end-stage heart failure because of dilated cardiomyopathy. J Cell Mol Med 2013; 17 (09) 1173-1187
    CrossrefPubMedGoogle Scholar
  • 27 Devaux Y, Vausort M, McCann GP. , et al. A panel of 4 microRNAs facilitates the prediction of left ventricular contractility after acute myocardial infarction. PLoS One 2013; 8 (08) e70644
    CrossrefPubMedGoogle Scholar
  • 28 Rybczynski M, Mir TS, Sheikhzadeh S. , et al. Frequency and age-related course of mitral valve dysfunction in the Marfan syndrome. Am J Cardiol 2010; 106 (07) 1048-1053
    CrossrefPubMedGoogle Scholar
  • 29 Brown OR, DeMots H, Kloster FE, Roberts A, Menashe VD, Beals RK. Aortic root dilatation and mitral valve prolapse in Marfan's syndrome: an ECHOCARDIOgraphic study. Circulation 1975; 52 (04) 651-657
    CrossrefPubMedGoogle Scholar
  • 30 Fichtlscherer S, De Rosa S, Fox H. , et al. Circulating microRNAs in patients with coronary artery disease. Circ Res 2010; 107 (05) 677-684
    CrossrefPubMedGoogle Scholar
  • 31 Fish JE, Santoro MM, Morton SU. , et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008; 15 (02) 272-284
    CrossrefPubMedGoogle Scholar
  • 32 Abu-Halima M, Hammadeh M, Backes C. , et al. Panel of five microRNAs as potential biomarkers for the diagnosis and assessment of male infertility. Fertil Steril 2014; 102 (04) 989-997.e1
    CrossrefPubMedGoogle Scholar
  • 33 Porciani MC, Attanasio M, Lepri V. , et al. Prevalence of cardiovascular manifestations in Marfan syndrome [in Italian]. Ital Heart J Suppl 2004; 5 (08) 647-652
    PubMedGoogle Scholar
  • 34 Kuosmanen SM, Hartikainen J, Hippeläinen M, Kokki H, Levonen AL, Tavi P. MicroRNA profiling of pericardial fluid samples from patients with heart failure. PLoS One 2015; 10 (03) e0119646
    CrossrefPubMedGoogle Scholar
  • 35 Dweep H, Sticht C, Pandey P, Gretz N. miRWalk--database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform 2011; 44 (05) 839-847
    CrossrefPubMedGoogle Scholar
  • 36 Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A. Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation 1996; 94 (11) 2708-2711
    CrossrefPubMedGoogle Scholar
  • 37 Lönnqvist L, Child A, Kainulainen K, Davidson R, Puhakka L, Peltonen L. A novel mutation of the fibrillin gene causing ectopia lentis. Genomics 1994; 19 (03) 573-576
    CrossrefPubMedGoogle Scholar
  • 38 Hayward C, Porteous ME, Brock DJ. A novel mutation in the fibrillin gene (FBN1) in familial arachnodactyly. Mol Cell Probes 1994; 8 (04) 325-327
    CrossrefPubMedGoogle Scholar
  • 39 Milewicz DM, Grossfield J, Cao SN, Kielty C, Covitz W, Jewett T. A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. J Clin Invest 1995; 95 (05) 2373-2378
    CrossrefPubMedGoogle Scholar
  • 40 Loeys BL, Chen J, Neptune ER. , et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005; 37 (03) 275-281
    CrossrefPubMedGoogle Scholar
  • 41 Stheneur C, Collod-Béroud G, Faivre L. , et al. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat 2008; 29 (11) E284-E295
    CrossrefPubMedGoogle Scholar
  • 42 Loeys BL, Schwarze U, Holm T. , et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006; 355 (08) 788-798
    CrossrefPubMedGoogle Scholar
  • 43 Pannu H, Tran-Fadulu V, Milewicz DM. Genetic basis of thoracic aortic aneurysms and aortic dissections. Am J Med Genet C Semin Med Genet 2005; 139C (01) 10-16
    CrossrefPubMedGoogle Scholar
  • 44 Doyle AJ, Doyle JJ, Bessling SL. , et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 2012; 44 (11) 1249-1254
    CrossrefPubMedGoogle Scholar
  • 45 Cannaerts E, van de Beek G, Verstraeten A, Van Laer L, Loeys B. TGF-β signalopathies as a paradigm for translational medicine. Eur J Med Genet 2015; 58 (12) 695-703
    CrossrefPubMedGoogle Scholar