NDT Advance Access first published online on April 11, 2008
This version published online on April 17, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn185
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Association between cytokine gene polymorphisms and outcomes in renal transplantation: a meta-analysis of individual patient data
1 Clinical Epidemiology Unit, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 2 Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Newcastle, NSW, Australia 3 Immunology Laboratory, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada 4 Division of Allergy, Clinical Immunology and Rheumatology, Department of Pediatrics, Escola Paulista de Medicina, Universidade Federal de Sâo Paulol, Sâo Paulo, Brazil 5 Department of Surgery, University of Mississippi, Medical Center, Jackson, MS, USA 6 Renal Transplant Unit, IDIBAPS, Hospital Clinic, Barcelona, Spain 7 Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, China 8 Transplantation Unit, Division of Nephrology 9 Department of Medicine, John Hunter Hospital, Newcastle, NSW, Australia
Correspondence and offprint requests to: Ammarin Thakkinstian, Clinical Epidemiology Unit, Rama VI Road, Rachatevi, Bangkok 10400, Thailand. Tel: 6622011762; Fax: 6622011284; E-mail: raatk{at}mahidol.ac.th
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Abstract |
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Background. Cytokine gene polymorphisms have been associated with poor outcomes after renal transplantation such as chronic allograft nephropathy (CAN), graft rejection (GR) and graft failure (GF), but the effects of these polymorphisms are still controversial. We therefore conducted a systematic review, with individual patient data (IPD) where possible, to determine the association between cytokine polymorphisms (TGF-β1, TNF-
and IL-10) and outcomes after renal transplantation.
Methods. Five investigators were willing to participate and provided IPD. The outcomes of interest were GF, GR and CAN. Subjects with at least one of these were classified as having poor outcomes. Heterogeneity of gene effects was assessed. Multiple logistic regression was applied to assess gene effects, adjusting for clinical variables such as HLA matching and age.
Results. One-thousand and eighty-seven subjects were included in the IPD meta-analysis. Pooled results showed no evidence of heterogeneity and indicated that the strongest variables determining poor outcomes are HLA mismatching (OR = 1.6–1.8 for 
3 HLA-A, -B, -DR mismatches compared with those with <3 mismatches) and age (OR = 1.2–1.4 for age 45 years or more). Incremental information on risk of a poor outcome is provided by the TGF-β1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0–2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-β1 at c10 and c25 were inferred and the C-C haplotype was a marker of a poor outcome (OR = 1.3, P = 0.177, 95% CI: 1.0–2.3). Three polymorphisms of the IL-10 gene at –1082, –819, –592 are in strong linkage disequilibrium with each other (correlation coefficients: 0.6–1) and inferred haplotypes between these three loci show some association, with ACC increasing the risk of poor events com- pared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9–1.6).
Conclusion. Pooled results to date suggest possible association between both the TGF-β1 c10 polymorphism and a 3-SNP-haplotype of IL-10 and poor outcomes in renal transplantation, but this needs to be confirmed in larger studies.
Keywords: cytokine polymorphisms; graft rejection; graft failure; individual-patient meta-analysis; renal transplantation
Received for publication: 22.11.07
Accepted in revised form: 10. 3.08