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

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 patients[2]. IFN-γ protected against the 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