Background: Cytokine-inducible SH-2 containing protein (CISH) is a member of suppressor of cytokine signaling (SOCS) family and involved in the negative regulation of IL-2 mediated signaling pathway. We postulated the polymorphism in CISH gene would influence the allograft outcomes.

Methods: Two single nucleotide polymorphisms in CISH gene, rs414171 (-292 A/T) and rs2239751 (+1320 A/C) were genotyped in 339 donor-recipient pairs of adult living-donor kidney transplant patients in Seoul National University Hospital from 1996 to 2009. Allograft outcomes included acute rejection (AR), estimated glomerular filtration rate (GFR) and graft loss.

Results: AR was identified in 62 (18.3%) recipients within 1 year and graft loss occurred in 27 (8.0%) cases over median follow-up of 5.8 years. There was no association with AR. Mean eGFR was 64.2±17.0 ml/min/1.73m² at 1 year after transplantation. eGFR tended to be lower in the group with donor rs2239751 AA genotypes for more than 10 years, after correcting for AR, year after transplantation, donor age, gender of donor and recipient, and immunosuppressant regimen (beta=-3.3, P=0.057, generalized estimating equations analysis). Graft survival rate was significantly lower in subjects with donor rs414171 TT genotype than TA+AA genotypes (hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.1-6.9, P=0.033 by Cox regression), and it was higher in subjects with donor rs2239751 AC+CC genotypes than AA genotype (HR 0.33, 95% CI 0.13-0.84, P=0.02).

Further mechanistic studies for roles of CISH in donor cell such as endothelial cells are needed.

Conclusion: Donor CISH polymorphism was associated with long-term graft survival in living donor kidney transplantation, suggesting that negative regulation of IL-2 signaling in allograft may be important in maintenance of functional integrity.

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