THE ROLE OF TNF-a POLYMORPHISM IN DEVELOPMENT OF HEART FAILURE AND TRANSPLANT REJECTION

THE ROLE OF TNF-a POLYMORPHISM IN DEVELOPMENT OF HEART FAILURE AND TRANSPLANT REJECTION
A. Bruggink, N. De Jonge, M. Tilanus, F. Gmelig-Meyling en R. De Weger
Departments of Pathology, Immunology en Heart Lung Institute, University Medical Cluster Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands

Tumor necrosis factor alpha (TNFa) is a pro-inflammatory cytokine, which is produced mainly by macrophages. Production of TNFa causes endothelial cell activation, up regulation of adhesion molecules and Major Histocompatibilty Complex (MHC) antigens. Overexpression of TNFa can induce dysfunctioning of the left ventricle and of cardiomyocytes. After transplantation TNFa as a T-helper 1 cytokine can contribute to cardiomyocyte damage. The TNF gene is localised in the Class III region of the MHC, telomeric of Class II and centromeric of Class I. In the promoter region of TNFa a number of polymorphisms occur, that influence the level of cytokine production and are therefore associated with the development of certain diseases. In this study the association of the polymorphisms at position -308, -240, and -238 (of patient and donor) is analysed in relation with HLA phenotype, the original cause of heart failure and rejection after transplantation in the first 6 months. In this study 31 patients with ischaemic heart failure (IHF), 33 patients with dilated cardiomyopathy ie (DCM) and 61 donors were screened for the TNFa promotor gene polymorphisms.
A G at position -308 (TNF1) is significantly associated with HLA DR4 en DR6. The substitution of a G to an A at position -308 (TNF2) is positively associated with HLA A1, B8 and DR3 haplotype. This confirms the data of previous studies. No association was found between TNFa polymorphism and IHF. However for patients suffering of DCM there seems to be trend to the presence of TNF2 at position -308. The other polymorfisms did not show a significant correlation. After transplantation there was no significant correlation between the number or severity of rejections and a certain polymorphism in the patient or the donor. However after transplantation of a donor heart with GA at position -308 the number of rejections is higher then in patients receiving a GG donor heart (AA is a rare genotype).