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References 1. Peker E, Kirimi E, Tuncer O, et al. Necrotizing fasciitis caused by Staphylococcus epidermidis in a neonate with extremely low birthweight. J Dermatol 2010;37(7):671-3. 2. Abbo O, Accadbled F, Guitard J, et al. Necrotizing fasciitis due to Pseudomonas aeruginosa in immunocompromised children. Pediatr Blood Cancer 2010;55(1):213-4. 3. Malbrain ML, Cheatham ML, Kirkpatrick A, et al. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome I: definitions. Intensive Care Med 2006;32(11):1722-32. 4. Cheatham ML, Malbrain ML, Kirkpatrick A, et al. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome II: recommendations. Intensive Care Med 2007;33(6): 951-62. 5. Baharestani MM. An overview of neonatal and pediatric wound care knowledge and considerations. Ostomy Wound Manage 2007; 53(6):34-6. 6. Aydin U, Ozgenel Y, Kanturk R. Vacuum-assisted closure therapy in newborn gangrene. J Plast Reconstr Aesthet Surg 2010;63(3):e277-9.

Cytokine Gene Polymorphisms in Childhood Dilated Cardiomyopathy: Interferon- gamma, Tumor Necrosis Factor-alpha and Transforming Growth Factor - beta 1 Genes Are Associated with the Disease in Turkish Patients Sibel Oguzkan Balci*1, PhD; Nilgun Col-Araz2, MD; Osman Baspinar3, MD; Tugce Sever1, MSc; Ayse Balat4, MD; Sacide Pehlivan1, PhD 1. Department of Medical Biology and Genetics, Faculty of Medicine, University of Gaziantep, Turkey 2. Department of Pediatrics, Faculty of Medicine, University of Gaziantep, Turkey 3. Department of Pediatric Cardiology, Faculty of Medicine, University of Gaziantep, Turkey 4. Department of Pediatric Nephrology, Faculty of Medicine, University of Gaziantep, Turkey Received: Marr 19, 2013; Accepted: Jun 28, 2013; First Online Available: Aug 14, 2013

Dilated cardiomyopathy (DCM) is a cardiac muscle disease with reduced left ventricular systolic function1]. Myocardial inflammation is the most common mechanism in the pathogenesis of cardiomyopathy in which cytokines may play an

important role[2]. The objective of this study was to investigate the associations between tumor necrosis factor-alpha (TNF-α, -308), transforming growth factor-beta 1 (TGF-β1, +10, +25), interleukin-10 (IL-10, -1082, -819, and -592), interleukin-6 (IL-6, -174), interferon-gamma (IFNγ, +874) gene polymorphisms and DCM. Sixteen children with DCM (3 months-13 years) and 21 healthy controls were tested for the cytokine genes with polymerase chain reactionsequence-specific primers (PCR-SSP). In our results, TNF-α (-308) A allele was higher in DCM (P=0.03). The frequency of TNF-α (-308) GG genotype (low expression) was significantly decreased in DCM (P=0.02). The children with DCM had significantly higher frequencies of IFN-γ (+874) TT genotype (high expression) and allele T while TA genotype (intermediate expression) was lower in patients (P=0.003, P=0.01 and P=0.04, respectively). Haplotype analyses showed that TT/GG and TC/GG ha plotypes of TGF-β1 (high expression) were significantly decreased while TC/GC, CC/GG and TT/GC (intermediate expression) haplotypes were increased (P=0.01 and P=0.04, respectively). There was no association between IL-6 and IL-10 genotypes/haplotypes and DCM (P>0.05). TNF-α is a strong proinflammatory and immunomodulatory cytokine that intervenes inflammatory diseases and is produced by activated macrophages[3]. Frequency of TNF-α allele A was found high in DCM[4]. TNF-α allele A (308) was found over-expressed in patients with end-stage non-ischemic myocardial dysfunction[5]. Tired et al did not find any association between TNF-α (-308) polymorphism and DCM[6]. In our study, allele A of TNF-α (-308) gene was found susceptible to DCM, while GG genotype of TNF-α (308) showed a protective effect against the disease. The production or activities of several cytokines are modulated by IFN-γ[7]. The AA homozygosity of IFN-γ (+874) T/A polymorphism was associated with poor prognosis in idiopathic DCM in older IFN-γ protected against the patients[2]. development of severe chronic myocarditis, pericarditis, and DCM after Coxackievirus B3 infection by reducing mast cell degranulation, and the profibrotic cytokines (IL-4, IL-1β, TGF-β1) in the heart[8]. In our study, the high expression of IFN-γ was found susceptible to DCM. We

* Corresponding Author; Address: Department of Medical Biology and Genetics, University of Gaziantep, 27310 Gaziantep, Turkey E-mail: [email protected] Iran J Pediatr; Vol 23 (No 5), Oct 2013 Published by: Tehran University of Medical Sciences (http://ijp.tums.ac.ir)

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hypothesized that IFN-γ might play a possible role in the immuno-inflammatory process of childhood DCM, although it is not clear whether these act to preserve or protect against further inflammatory injury. IL-6 is one of the proinflammatory cytokines with many systemic effects, including [9] cardiovascular system . The GG and GC genotypes of IL-6 (-174) are associated with increased levels of IL-6, while CC with decreased expression[10]. IL-6 levels were significantly associated with all outcomes of heart disease in adults[11]. IL-6 (-174) polymorphism was associated with LVESD and LVEDD in DCM[8]. Although allele C was higher in our patient group, there was borderline statistical significance between the groups (P=0.0590). IL-10 is a regulatory cytokine which inhibits the production of IFN-γ and TNF-α and antagonizes the proinflammatory cytokine response[12]. The diagnosis of DCM has been associated with a reduction in IL-10 plasma levels, indicating its protective role in cytokine activation[13]. However, recent studies have suggested that IL-10 polymorphisms are not associated with DCM[2,4], in agreement with our results. TGF-β1 is an anti-inflammatory cytokine that might play a major role in the immune modulation of heart function[6]. TGF-β1 expression is increased in the myocardium of patients with DCM[14]. TGF-β1 polymorphisms were correlated with better exercise capacity, and heart failure symptoms[2]. Tiret et al found no relationship between TGF-β1 gene polymorphism and DCM[6]. This study indicates that the high expression of TGF-β1 had a protective effect against the DCM, while intermediate expression had susceptibility to the disease. Fairweather et al reported that IFNγ protected against the development of DCM after infection by reducing profibrotic cytokines like TGF-β1[8]. We conclude that the increase in the expression of IFN-γ and TNF-α genes may be associated with the etiopathogenesis of DCM; however, the increase in the expression of TGF-β1 gene may play a protective role against the development of this disease. Key words: Cytokines; Dilated cardiomyopathy; Gene Polymorphism

References 1. Nugent AW, Daubeney DE, Chandras P, et al. The epidemiyology of childhood cardiomiyopathy in Australia. N Engl J Med 2003;348(17):1639-46. 2. Adamopoulos S, Kolokathis F, Gkouziouta A, et al. Cytokine gene polymorphisms are associated with markers of disease severity and prognosis in patients with idiopathic dilated cardiomyopathy. Cytokine 2011;54(1):68-73. 3. Vadlamani L, Iyengar S. Tumour necrosis factor α polymorphism in heart failure/cardiomyopathy. Congest Heart Fail 2004;10(6):289-92. 4. Ito M, Takahashi H, Fuse K, et al. Polymorphisms of tumor necrosis factor-α and interleukin 10 genes in Japanese patients with idiopathic dilated cardiomyopathy. Jpn Heart J 2000;41(2):83-91. 5. Densem CG, Hutchinson IV, Yonan N, et al. Tumor necrosis factor alpha gene polymorphism: a predisposing factor to non-ischaemic myocardial dysfunction? Heart 2002;87(2):153-5. 6. Tiret L, Mallet C, Poirier O, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2000;35(1):29-35. 7. Schroder K, Hertzog PJ, Ravasi T, et al. Interferongamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004;75(2):163-89. 8. Fairweather D, Frisancho-Kiss S, Yusung SA, et al. Interferon-γ protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-β1, interleukin-1 β, and interleukin-4 in the heart. Am J Pathol 2004;165(6):1883-94. 9. Fonseca JE, Santos MJ, Canhao H, et al. Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev 2009;8(7):538-42. 10. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphism in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic onset juvenile chronic arthritis. J Clin Invest 1998;102(7):1369-76. 11. Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events: result from the health ABC study. Circulation 2003;108(19):2317-22. 12. Couper KN, Blount DG, Riley EM. Il-10: The master regulator of immunity to infection. J Immunol 2008; 180(9):5771-7. 13. Adamopoulos S, Parissis JT, Paraskevaidis I, et al. Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy. Eur Heart J 2003;24(24):2186-96. 14. Aharinejad S, Krenn K, Paulus P, et al. Differantial role of TGF-β1/bFGF and ET-1 in graft fibrosis in heart failure patients. Am J Transplant 2005;5(9):2185-92.

Iran J Pediatr; Vol 23 (No 5), Oct 2013 Published by: Tehran University of Medical Sciences (http://ijp.tums.ac.ir)

Cytokine Gene Polymorphisms in Childhood Dilated Cardiomyopathy: Interferon- gamma, Tumor Necrosis Factor-alpha and Transforming Growth Factor - beta 1 Genes Are Associated with the Disease in Turkish Patients.

Cytokine Gene Polymorphisms in Childhood Dilated Cardiomyopathy: Interferon- gamma, Tumor Necrosis Factor-alpha and Transforming Growth Factor - beta 1 Genes Are Associated with the Disease in Turkish Patients. - PDF Download Free
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