Cytokine gene polymorphisms in heart transplantation: association of low IL-10 production genotype with Quilty effect.

ABSTRACT

BACKGROUND: Cytokines are important modulators of post-transplant, allogeneic immune responses. In heart transplantation, endomyocardial biopsies allow monitoring of histologic and immunologic events that occur inside the graft; their correlation with risk factors condition graft outcome. Recent reports indicate that various cytokine gene allelic polymorphisms control the number of cytokines produced and may be associated with graft outcome. METHODS: We studied 71 heart transplant recipients between December 1985 and December 2000. We used sequence-specific primers (SSP) polymerase chain reaction to study interleukin-10 (IL-10) polymorphisms at -1082 (G/A), -819 (C/T), and -592 (C/A); tumor necrosis factor alpha (TNF-alpha) at -308 (G/A) and -238 (G/A); transforming growth factor beta (TGF-beta) variants at codon 10 (C/T) and codon 25 (G/C); and interferon-gamma (IFN-gamma) polymorphisms at +874 (T/A). We determined the association of allele, genotype, and haplotype frequencies with the presence of histologically proven rejection episodes (according to International Society for Heart and Lung Transplantation criteria) and the presence of Quilty lesions in endomyocardial biopsy specimens. RESULTS: We found no association between the polymorphisms studied and the frequency and severity of acute and chronic rejection episodes. However, the gene frequency of allele A at IL-10 -1082, associated with decreased IL-10 production, was increased in patients with Quilty lesions (p = 0.0027, odds ratio = 2.98). Similarly, we found more AA homozygous individuals, compared with AG heterozygous and GG homozygous individuals (p = 0.0017), among patients with Quilty effect. The ATA and ACC IL-10 haplotypes also were associated with Quilty effect (p = 0.0051). CONCLUSIONS: These results suggest that genetically controlled decreased IL-10 production predisposes to the development of Quilty lesions. The decreased negative regulatory effect of IL-10 on T cells and macrophages may result in enhanced graft infiltration.