Cytokine gene polymorphisms are associated with markers of disease severity and prognosis in patients with idiopathic dilated cardiomyopathy Stamatis Adamopoulos a , Fotis Kolokathis b , Angeliki Gkouziouta a , Panagiota Georgiadou a,⇑ , Antigoni Chaidaroglou c , George K. Karavolias a , Dimitrios Degiannis c , Vassilis Voudris a , Dimitrios Th. Kremastinos b a 2nd Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece b 2nd University Department of Cardiology, Medical School, Attikon General Hospital, University of Athens, Athens, Greece c Molecular Immunopathology and Histocompatibility Laboratory, Onassis Cardiac Surgery Center, Athens, Greece article info Article history: Received 19 October 2009 Received in revised form 21 December 2010 Accepted 2 January 2011 Available online 1 February 2011 Keywords: Cytokines Polymorphisms Idiopathic dilated cardiomyopathy abstract Aims: To identify potential genetic associations of five cytokine gene polymorphisms with disease sever- ity and prognosis in patients with idiopathic dilated cardiomyopathy (DCM). Methods and results: Eighty patients with DCM were genotyped for transforming growth factor beta1 (TGF-b1) +869 T/C (codon10 Leu ? Pro), TGF-b1 +915 G/C (codon25 Arg ? Pro), interleukin (IL)-6 À174G/C, tumor necrosis factor-alpha (TNF-a) À308A/G, interferon-gamma (IFN-c) +874T/A, IL-10 À1082A/G, IL-10 À819T/C and IL-10 À592A/C gene polymorphisms. In homozygous TT patients for TGF-b1 +869 T/C polymorphism mean VO 2 max was significantly higher than in CC homozygous patients (25.67 ± 6.73 ml/kg/min vs. 20.29 ± 6.35 ml/kg/min, p = 0.046), which remained significant only for patients younger than 39 years old after adjusting for age and sex (p = 0.009). C carriers of TGF-b1 +915 G/C polymorphism are 4.2 times more likely to be in a worse NYHA stage (III–IV) than non C carriers [OR: 4.25, 95% CI (1.53–11.80), p = 0.006]. Patients GG homozygous for IL-6 À174G/C polymorphism pre- sented greater left ventricle end-systolic (p = 0.018) and end-diastolic (p = 0.04) diameters in comparison to the CC homozygous. The AA homozygote for IFN-c +874T/A polymorphism (p = 0.02) and the combi- nation of the TGF-b1 +869 T/C and TGF-b1 +915 G/C genotypes were associated with adverse outcome (p = 0.014). Conclusion: Specific cytokine gene polymorphisms seem to be associated with worse prognosis as well as with measures of disease severity in DCM. Ó 2011 Elsevier Ltd All rights reserved. 1. Introduction Extensive evidence supports the involvement of cytokines in the inflammatory and immune responses mediating the pathogen- esis of idiopathic dilated cardiomyopathy (DCM) [1,2]. The genetic contribution of cytokine network to the prevalence and the pro- gression of this disease have been investigated by a number of studies [3–5]. Several polymorphisms of cytokine genes or gene promoters, may affect gene transcription, influencing the in vivo and in vitro cytokine production [3–5]. Among the major circulating cytokines implicated in the devel- opment of the syndrome are the proinflammatory cytokines tumor necrosis factor-a (TNF-a), interleukin (IL)-6 and interferon-c (IFN- c), which have been found to be upregulated in heart failure [2]. TNF-a and IL-6 have also been shown to be predictors for cardio- vascular outcome whereas a strong association has been found be- tween IFN-c polymorphism and susceptibility to DCM [6,7]. Levels of transforming growth factor-b1 (TGF-b1) – an anti-inflammatory cytokine – are elevated in the circulation of patients with conges- tive heart failure and have been associated with maladaptive ven- tricular remodelling [8]. The diagnosis of DCM has been associated with a reduction in IL-10 plasma levels, indicating its protective role in cytokine activation [9]. The present study is a pilot study, addressing the hypothesis that cytokine gene polymorphisms may reflect the severity and progression of DCM, ultimately leading to adverse outcome. In this respect, we examined polymorphisms of the most important inflammatory cytokines-TGF-b1, IL-6, IL-10, TNF-a and IFN-c in 80 patients with DCM. We investigated whether these gene poly- morphisms are associated with patients’ symptoms and exercise capacity, as expressed by peak oxygen uptake (VO 2 max) as well as with echocardiographic indexes of cardiac remodelling and con- tractile performance, as expressed mainly by left ventricular end 1043-4666/$ - see front matter Ó 2011 Elsevier Ltd All rights reserved. doi:10.1016/j.cyto.2011.01.004 ⇑ Corresponding author. Address: 2nd Department of Cardiology, Onassis Cardiac Surgery Center, 356 Syngrou Avenue, 176 74 Athens, Greece. Tel.: +30 210 9493372; fax: +30 210 9493373. E-mail address: pg171@hlk.forthnet.gr (P. Georgiadou). Cytokine 54 (2011) 68–73 Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/issn/10434666