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Infections with cardiotropic viruses are often accompanied by ongoing autoimmune reactions in the myocardium and occasionally result in the transition from chronic myocarditis to dilated cardiomyopathy (DCM), a heart disease characterized by enlarged ventricles and reduced systolic function. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor expressed on the surface of activated T cells, which competes with co-stimulatory CD28 for binding to B7 receptors on antigen-presenting cells. The aim of this epidemiological study was to assess whether single nucleotide polymorphisms (SNPs) within the CTLA-4 gene are associated with the diagnosis and disease course of DCM. A total of 152 DCM patients and 221 healthy blood donors used as controls were tested for the presence of the known +49-(CT42) polymorphism in the CTLA-4 gene by means of denaturing gradient gel electrophoresis (DGGE). It was found that the G/G genotype of the CT42 polymorphism was significantly more frequent in DCM patients as compared to controls (24 out of 152 patients (16%) versus 16 out of 221 controls (7%), p=0.029). At follow-up one year after study inclusion, the left-ventricular ejection fraction and the end-diastolic diameter of the left ventricle had generally improved, however, there was no difference between DCM patients carrying the CT42 G/G genotype versus other genotypes (n=199). In contrast to the CT42 SNP, no statistically significant association was found between the CT60 polymorphism in the 3 ́-untranslated region in exon 4 of the CTLA-4 gene and the diagnosis of DCM. In summary, these data indicate that the common CTLA-4 polymorphism CT42 confers susceptibility for DCM, but appears not to influence the course of the disease one year after diagnosis. The G/G genotype encodes for a Thr17Ala variant in the amino-terminally signal leader peptide of the CTLA-4 molecule, suggesting that a single aminoacid exchange from threonine to alanine at this position may be associated with unbalanced autoimmune reactions against myocardial tissue which ultimately leads to progressive destruction of cardiac myocytes and the development of dilated cardiomyopathy.