Association of cytokine polymorphisms with subclinical progressive chronic allograft nephropathy in Japanese renal transplant recipients: Preliminary study

Abstract

Background: The present study calculated the risk of developing subclinical progressive chronic/sclerosing allograft nephropathy (CAN) under tacrolimus-based immunosuppression according to genetic polymorphisms of cytokines and growth factors, and clinical events including delayed graft function (DGF), acute rejection (AR) and cytomegalovirus (CMV) infection. Methods: The subjects were 50 recipients with stable graft function more than one year after renal transplantation. The criteria for subclinical progressive CAN were CAN grade 2 or 3 changes on Banff classification and stable serum creatinine (SCr) levels. Ten genetic polymorphisms were assessed. Results: Eleven patients (22.0%) developed progressive CAN. The mean ages and SCr levels of recipients with and without progressive CAN were 41.2 and 47.1 years, and 1.46 and 1.22 mg/dL, respectively. There were no significant differences in donor age, number of HLA mismatches, DGF or CMV infection. Although the rate of AR episode seemed to be greater in patients with subclinical progressive CAN, the difference did not reach significance (P = 0.093). The frequencies of the interleukin (IL)-2 T-330G TT genotype (P = 0.046) and IL-4 C-590T C allele (P = 0.092) were higher in patients with progressive CAN. In univariate analysis, the presence of IL-2 T-330G TT (OR 4.57, P = 0.044) was associated with CAN development. Conclusion:The presence of IL-2 T-330G TT genotype may be a risk factor for CAN. Further studies with a large number of subjects and analyses of many cytokine polymorphisms would contribute to the ability to make prognostic determinations or tailor immunomodulatory regimens after renal transplantation.

Inflammation in the setting of chronic allograft dysfunction post‐kidney transplant: phenotype and genotype

“…Previous studies have found SNPs that are associated with CGD. These SNPs include rs699 in AGT , rs2069762 in IL2 in a Japanese population , rs1801131 in MTHFR , rs1800629 in TNFA . These previously published studies are much smaller than the present study.…”

PharmGKB summary

“…However, variations within cytokine genes also show associations with side effects and outcomes. These include IL-6 , where GG homozygotes at position − 174 had an increased risk of new-onset diabetes after transplantation [129], IL-12B , where the C allele in rs3212227 conferred increased risk for cytomegalovirus infection with an odds ratio (OR) of 1.52 [130], and IL-2 , where TT homozygotes at position 330 had a higher risk of developing chronic allograft nephropathy [131]. Patients in these studies were treated with either tacrolimus or cyclosporine as part of their immunosuppressive regime.…”

Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy

“…Single studies have been able to document a well-defined relationship between several SNPs and clinical outcomes (Table 8 )[ 67 , 73 , 77 - 79 ]. However, these genes have not been validated by other studies, and these genes as well as other genes that have been described in this review are only recommended candidates for future studies (Table 9 )[ 80 ].…”