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Gene polymorphisms in renal transplantation Dmitrienko, Svetlana

Abstract

Despite optimal HLA matching and advances in immunosuppressive therapy, acute rejection remains a leading cause of transplant failure. Increasing evidence suggests that T-cell activation and response to immunosuppression vary widely between individuals, and that these functional differences may be related at least in part to polymorphisms within critical immune response genes. Testing for these polymorphisms may therefore provide a simple and clinically important method for predicting rejection risk and guiding therapy in renal transplantation. Genetic polymorphisms of two groups of genes (T-cell signaling molecules and cytokine genes) were studied in renal transplant patients who did (AR group) or did not (NR group) experience acute rejection episodes during the first year after transplant. CTLA-4, CD45, and CD40L signaling molecules and TGF-β1, IL-10, TNF-α, and IFN-γ cytokine gene polymorphisms were examined. PCR-RFLP, SNP, and fragment length analysis of dinucleotide repeats were used to study the relationship between genetic polymorphisms and the frequency of acute rejection. The allele frequencies at each gene locus were determined for the study groups and compared to the control population by Fisher's exact test. Multiple logistic regression analysis was performed using statistical language R, version 1.8.0 (2004), software. There was no significant difference in the frequency of the CTLA-4 (-318 C/T and +49 A/G), and TGF-pi (+600 T/C and +650 G/C) genes RFLP in patients with acute renal transplant rejection in a comparison with patients with no rejection. The variant (G⁺⁷⁷) allele of the CD45 gene was not detected in the study population. Univariate analysis of SNP polymorphisms at the IL-10 (-1082 A/G) and TNF-a (-308 A/G) genes, and LFN-γ and CD40L dinucleotide repeat polymorphisms did not reach a level of statistical significance. However, multiple logistic regression analysis which incorporated demographic and clinical data, demonstrated a significant difference for the CD40L 157 1* and 2* alleles between the AR and NR groups (OR=0.58 and OR=0, respectively; p value=0.005), with the proportion of patients carrying the CD40L 157 allele being higher in the NR than in the AR group. This finding suggests that the CD40L 157 allele may have a protective effect in renal transplantation and requires further investigation.

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