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Cardiovascular disease is the most common cause of death in today's society. Heart transplantation is the only available treatment for patients suffering from end-stage congestive heart failure (CHF). Causes underlying the development of CHF are still unknown, but it has been suggested that proinflammatory cytokines play an important role. In the context of transplantation, proinflammatory T-helper 1 cytokines like TNF-α and IL-2 that mediate the cellular immune response are believed to be involved in acute graft rejection. On the other hand, Th2 cytokines, like IL-4, IL-6 and IL-10, induce tolerance, by down-regulating the Th1 response and cytokine production. Cytokine release by macrophages, lymphocytes and other cell types in the microenvironment of the graft, especially the balance between Th1 and Th2, is thought to be critical for the development of acute rejection. Production of cytokines has been shown to be under genetic control of single nucleotide polymorphisms (SNP) in mainly the promoter regions of cytokine genes. Genotypes of these SNP were shown to control the differential production of these cytokines, leading to a wide variety of cytokine patterns among individuals. Since levels of these cytokines affect the Th1 / Th2 balance, genotypes may be related to acute allograft rejection. Many studies have shown an association between cytokine gene polymorphisms and the development of several infections, allergies and autoimmune diseases. Also, associations between SNP in different cytokine genes and transplant rejection have been extensively studied. In our lab, SNP in the genes of TNF-α, TGF-β, IL- 4 and IL-10 were studied in a panel of 70 cardiac transplant patients and 61 of their donors. These data are discussed in the context of literature data.

Background--Connective tissue growth factor (CCN2; CTGF) is a newly identified growth factor, which is involved in the regulation of wound repair and fibrosis. Because there is variation among individuals with respect to tissue response to injury, genetic factors might be involved in the final outcome of tissue repair or scarring. For example, polymorphisms in the promoter region of genes, such as those encoding transforming growth factor β1 (TGF-β1), interleukin 10 (IL-10), and tumour necrosis factor α (TNF-α), influence transcriptional responses and are thought to contribute to the dysregulation of these genes in pathological conditions.Aim--To investigate whether the promoter region of the ccn2 (ctgf) gene contains polymorphic sequences that might account for differential expression.Materials/Methods--Seventy seven human DNA samples were sequenced--45 were from healthy controls and 32 were from patients with ischaemic heart disease (IHD)--using M13 tailed sequence specific ccn2 (ctgf) primers for amplification of a 600 bp fragment upstream of the transcription start site. Amplicons were bidirectionally sequenced with a dye primer M13 forward and reverse sequencing kit.Results--A C to G substitution was identified at position -132 in one of the patients with IHD. Moreover, in five of the 32 patients with IHD and in six of the 45 healthy controls, a G to C polymorphism was found at position -447. These substitutions at -132 and -447 are thought to lie within predicted binding domains for the transcription factors Pbx-1 and MZF1, respectively. In addition, insertions at position -43 (G), -47 (C), -71 (G) and a C to T substitution at position -198 were found in all DNA samples compared with the published ccn2 (ctgf) promoter sequence. These corrections do not involve sequences predicted to function as transcription factor binding sites.Conclusion--Sequence analysis of the ccn2 (ctgf) promoter of 77 human DNA samples has revealed corrections and polymorphic sites. The latter lie within putative regulatory elements.