Association of pro/anti-inflammatory cytokine gene variants in renal transplant patients with allograft outcome and cyclosporine immunosuppressant levels

T-helper (Th) type 1/Th2 cytokines are key mediators in induction/effecter phases of all immune and inflammatory responses playing role in acute/chronic renal allograft rejection. Association studies lead to identification of patient risk profiles enabling individualization of level of immunosuppressions. We investigated the association of allograft rejection with interleukin-2 (IL-2), IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha) -308, transforming growth factor-beta (TGF-beta) (C-del, codon 10 and 25) gene variants in 184 renal transplant recipients and 180 controls. These cytokine genotypes were also evaluated with cyclosporine levels (C2) at one month in 135 stable recipients. High producing genotypes B1B1 of IL-4 and AA of TNF-alpha alpha308 showed significant association with rejection of allograft. The dose-adjusted C2 levels were significantly lower in patients with the high producing genotype T/T of IL-2 and heterozygous G/C of TGF-beta codon 25 (P = 0.012 and 0.010, respectively). Haplotype frequencies were comparable in subjects for TGF-beta codon-10 and 25. Combined inter-gene interaction showed high risk for rejection in recipients with high producing genotype B1B1 of IL-4 and AA of TNF-alpha and high TNF-alpha (AA) with low TGF-beta (CC or Pro/Pro). In conclusion, association of IL-4 VNTR and TNF-alpha -308 suggested the involvement of these cytokines contributing to pathogenesis of allograft rejection. Recipients with TT genotype of IL-2 and GC of TGF-beta codon 25 having low C2 levels may require higher cyclosporine dosage. Combined analysis of gene-gene interaction demonstrated synergistic effect of cytokines increasing risk for rejection. Thus, this information may help in pre-assessment of allograft outcome and to optimize cyclosporine therapy in post-transplant patients.