medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2018.05.13-18medgen-435Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHЭффективность новых плазменных биомаркеров FGF-21 и GDF-15 в дифференциальной диагностике митохондриальных заболеванийEfficiency of new plasma biomarkers FGF-21, GDF-15 in differential diagnostic of mitochondrial diseasesЦыганковаП. Г.TsygankovaP. G.polgamma@yandex.ruИткисЮ. С.ItkisYu. S.noemail@neicon.ruКрыловаТ. Д.KrylovaT. D.noemail@neicon.ruЗахароваЕ. Ю.ZakharovaE. Yu.noemail@neicon.ruФГБНУ «Медико-генетический научный центр»РоссияResearch centre for medical geneticsRussian Federation2018060620181751318Copyright © Цыганкова П.Г., Иткис Ю.С., Крылова Т.Д., Захарова Е.Ю., 20182018Цыганкова П.Г., Иткис Ю.С., Крылова Т.Д., Захарова Е.Ю.Tsygankova P.G., Itkis Y.S., Krylova T.D., Zakharova E.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/435

Введение. Циркулирующие плазменные цитокины FGF-21 и GDF-15 - активно исследуемые регуляторы клеточного метаболизма. Несколько исследований показали, что тесты по определению этих маркеров высокочувствительны и специфичны для диагностики митохондриальных заболеваний, особенно с нервно-мышечными проявлениями. Митохондриальные болезни - клинически и генетически гетерогенная группа заболеваний. Целью исследования являлось изучение роли данных маркеров в дифференциальной диагностике группы митохондриальных болезней (МБ). Исследуемая группа включала 107 пациентов с МБ, и контрольную выборку. Результаты. Концентрации FGF-21 и GDF-15 в группе пациентов с МБ были достоверно выше, чем в контроле. GDF-15 показал более высокую чувствительность и специфичность (0,89; 0,88; AUC = 0,932), чем FGF-21 (0,75; 0,69; AUC = 0,82). Особенно резкое повышение обоих маркеров (в 100-200 раз) было отмечено в группе митохондриальных гепатопатий, у GDF-15 выявлена способность различить некоторые другие формы МБ между собой.

Introduction. Plasma circulating cytokines FGF-21 and GDF-15 are recently described and actively investigated cell’s metabolism regulators. They both have endocrine function and highly expressed in liver upon stress and starvation. Several studies established these markers as highly sensitive and specific for diagnosis of patients with mitochondrial diseases, especially those with prominent muscle system involvement. Mitochondrial diseases are clinically and genetically heterogeneous group of diseases. Aim. In our study we aimed to reveal the role of this markers in differential diagnostic of mitochondrial diseases. We measured plasma FGF-21 and GDF-15 concentration in 107 patients with genetically confirmed primary mitochondrial disease and control group. Results. The concentration of FGF-21 and GDF-15 in the group of patients with mitochondrial diseases was significantly higher than in the control. GDF-15 showed higher sensitivity and specificity (0.89, 0.88, AUC = 0.932) than FGF-21 (0.75, 0.69, AUC = 0.82). Especially sharp increase of both markers (100-200 times) was noted in the group of mitochondrial hepatopathies, GDF-15 showed the ability to distinguish some other forms of mitochondrial disease among themselves.

митохондриальные биомаркерымитохондриальные гепатопатиимитохондриальные болезниFGF-21GDF-15mitochondrial biomarkersmitochondrial hepatopathiesmitochondrial encephalopathiesFGF-21GDF-15ReferencesSchaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders-past, present and future. Biochim Biophys Acta. 2004; 1659:115-120.Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders-past, present and future. Biochim Biophys Acta. 2004; 1659:115-120.Gorman GS1, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015 May;77(5):753-9.Gorman GS1, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015 May;77(5):753-9.Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Wong LJ, Cohen BH, Naviaux RK. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab. 2008 May;94(1):16-37.Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Wong LJ, Cohen BH, Naviaux RK. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab. 2008 May;94(1):16-37.DiMauro S1, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol. 2013 Aug;9(8):429-44.DiMauro S1, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol. 2013 Aug;9(8):429-44.Suomalainen A. Fibroblast growth factor 21: a novel biomarker for human muscle-manifesting mitochondrial disorders. Expert Opin Med Diagn. 2013 Jul;7(4):313-7Suomalainen A. Fibroblast growth factor 21: a novel biomarker for human muscle-manifesting mitochondrial disorders. Expert Opin Med Diagn. 2013 Jul;7(4):313-7Fujita Y, Ito M, Kojima T et al. GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion. 2014; 20:34-42.Fujita Y, Ito M, Kojima T et al. GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion. 2014; 20:34-42.Kalko SG, Paco S, Jou C et al. Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies. BMC Genomics 2014; 15:91.Kalko SG, Paco S, Jou C et al. Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies. BMC Genomics 2014; 15:91.Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, Kojima T, Ito M, Tanaka M, Saiki R, Koga Y. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol. 2015 Nov;78(5):814-23.Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, Kojima T, Ito M, Tanaka M, Saiki R, Koga Y. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol. 2015 Nov;78(5):814-23.Montero R, Yubero D, Villarroya J. GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction. PLoS One. 2016 Feb 11;11(2): e0148709.Montero R, Yubero D, Villarroya J. GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction. PLoS One. 2016 Feb 11;11(2): e0148709.Davis RL, Liang C, Sue CM. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology. 2016 May 24;86(21):2010-5.Davis RL, Liang C, Sue CM. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology. 2016 May 24;86(21):2010-5.Fisher FM, Maratos-Flier E. Understanding the Physiology of FGF21. Annu Rev Physiol. 2016;78: 223-41.Fisher FM, Maratos-Flier E. Understanding the Physiology of FGF21. Annu Rev Physiol. 2016;78: 223-41.Ji K, Zheng J, Lv J, Xu J, Ji X, Luo YB, Li W, Zhao Y, Yan C. Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1a pathway. Free Radic Biol Med. 2015 Jul; 84:161-70.Ji K, Zheng J, Lv J, Xu J, Ji X, Luo YB, Li W, Zhao Y, Yan C. Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1a pathway. Free Radic Biol Med. 2015 Jul; 84:161-70.Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG. Growth differentiation factor-15/ macrophage inhibitory cytokine induction after kidney and lung injury. Shock. 2005; 23: 543Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG. Growth differentiation factor-15/ macrophage inhibitory cytokine induction after kidney and lung injury. Shock. 2005; 23: 543Strelau J, Bоttner M, Lingor P, Suter-Crazzolara C, Galter D, Jaszai J et al. GDF-15/MIC-1 a novel member of theTGF-beta superfamily. J Neural Transm Suppl. 2000; 273-6.Strelau J, Bоttner M, Lingor P, Suter-Crazzolara C, Galter D, Jaszai J et al. GDF-15/MIC-1 a novel member of theTGF-beta superfamily. J Neural Transm Suppl. 2000; 273-6.Moore AG, Brown DA, Fairlie WD, Bauskin AR et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab. 2000 Dec; 85(12): 4781-8.Moore AG, Brown DA, Fairlie WD, Bauskin AR et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab. 2000 Dec; 85(12): 4781-8.Krawczyk M, Zimmermann S, Hess G, Holz R, Dauer M, Raedle J, Lammert F, Grunhage Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease. F.PLoS One. 2017 Mar 16;12(3): e0173506.Krawczyk M, Zimmermann S, Hess G, Holz R, Dauer M, Raedle J, Lammert F, Grunhage Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease. F.PLoS One. 2017 Mar 16;12(3): e0173506.Krautbauer S, Rein-Fischboeck L, Haberl EM, Pohl R, Wiest R, Buechler C. Circulating fibroblast growth factor 21 in patients with liver cirrhosis. Clin Exp Med. 2017 Jul 25.Krautbauer S, Rein-Fischboeck L, Haberl EM, Pohl R, Wiest R, Buechler C. Circulating fibroblast growth factor 21 in patients with liver cirrhosis. Clin Exp Med. 2017 Jul 25.Wollert KC, Kempf T, Wallentin L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem. 2017; 63: 140-151Wollert KC, Kempf T, Wallentin L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem. 2017; 63: 140-151Baggen VJ, van den Bosch AE, Eindhoven JA, Schut AW, Cuypers JA, Witsenburg M, de Waart M, van Schaik RH, Zijlstra F, Boersma E et al. Prognostic value of N-terminal Pro-B-type natriuretic peptide, Troponin-T, and growth-differentiation factor 15 in adult congenital heart disease. Circulation. 2017; 135: 264-279Baggen VJ, van den Bosch AE, Eindhoven JA, Schut AW, Cuypers JA, Witsenburg M, de Waart M, van Schaik RH, Zijlstra F, Boersma E et al. Prognostic value of N-terminal Pro-B-type natriuretic peptide, Troponin-T, and growth-differentiation factor 15 in adult congenital heart disease. Circulation. 2017; 135: 264-279

The authors declare that there are no conflicts of interest present.