Analysis of cytokine gene polymorphisms in recipient's matched with living donors on acute rejection after renal transplantation

Despite advances in immunosuppressive therapy in last few years, allograft rejection still remains the concern for kidney graft failure. Cytokines are key mediators in the induction and effector phases of all immune and inflammatory responses. They are not allospecific so both recipient as well as donor cells may be subjected to cytokine changes. We sought to ascertain whether IL-1B -511, IL-1B +3954, TNF-A -308, TGF-B Codon 10 and 25, IL-2 -330, IL-6 -174, IL-10 -1082, IL-10 -819 (SNPs), IL-1RN, IL-4 (VNTR) and TGF-B C-del (deletion) genes in two hundred subjects including recipients and their live matched donors influence renal allograft outcome. Screening was performed using PCR-RFLP and amplification refractory mutation system (ARMS-PCR). The risk for rejection appeared significant amongst recipients for pro-inflammatory cytokines IL-1B + 3954 (P = 0.045) and TNF-A -308 (0.031). No association of cytokine gene variants with rejection was observed in donors group. Further evaluating combinational effect of TNF-A (-308), IL-4 and IL-10 (-819) genes with the risk of allograft rejection showed no additive influence. Haplotype analysis between IL-1 gene cluster, TGF-B Codon 10 and 25 and IL-10 -1082 and -819 revealed that haplotypes of IL-1 gene 240-T-C, 410-T-C and 410-T-T showed very high risk among the recipients (> 16, > 5 and > 12 folds risk respectively) when compared to donors. Interestingly, all these three haplotypes contained the variant allele T* of IL-B -511. In conclusion, our results suggest that high producing genotypes of pro-inflammatory cytokine genes in recipients have risk for allograft rejection. Lack of association in donors may be suggestive of having no conspicuous role in allograft outcome. Further analysis of diversity in haplotype variations in large populations could conceivably provide the basis for defined approaches to limit the rejections.