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
Article Notes and Dates
Iranian Journal of Pediatrics: October 31, 2013,
; 603-604.Published Online: August 14, 2013
Article Type: Letter; Received: March 19, 2013; Accepted: June 28, 2013
To Cite :
A, et al. 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,
Iran J Pediatr.
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. 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 (IFN-γ, +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 reaction-sequence-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. Frequency of TNF-α allele A was found high in DCM. TNF-α allele A (-308) was found over-expressed in patients with end-stage non-ischemic myocardial dysfunction. Tired et al did not find any association between TNF-α (-308) polymorphism and DCM. 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. The AA homozygosity of IFN-γ (+874) T/A polymorphism was associated with poor prognosis in idiopathic DCM in older patients. 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. In our study, the high expression of IFN-γ was found susceptible to DCM. We hypothesized that IFN-γ might play a possible role in the immuno-inï¬ammatory process of childhood DCM, although it is not clear whether these act to preserve or protect against further inï¬ammatory injury.
IL-6 is one of the proinflammatory cytokines with many systemic effects, including cardiovascular system. The GG and GC genotypes of IL-6 (-174) are associated with increased levels of IL-6, while CC with decreased expression. IL-6 levels were significantly associated with all outcomes of heart disease in adults. IL-6 (-174) polymorphism was associated with LVESD and LVEDD in DCM. 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. The diagnosis of DCM has been associated with a reduction in IL-10 plasma levels, indicating its protective role in cytokine activation. 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. TGF-β1 expression is increased in the myocardium of patients with DCM. TGF-β1 polymorphisms were correlated with better exercise capacity, and heart failure symptoms. Tiret et al found no relationship between TGF-β1 gene polymorphism and DCM. 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 IFN-γ protected against the development of DCM after infection by reducing profibrotic cytokines like TGF-β1.
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.
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