Thakkinstian Ammarin, Dmitrienko Svetlana, Gerbase-Delima Maria, McDaniel D Olga, Inigo Pablo, Chow Kai Ming, McEvoy Mark, Ingsathit Atiporn, Trevillian Paul, Barber William Henry, Attia John
Clinical Epidemiology Unit, Rama VI Road, Rachatevi, Bangkok 10400, Thailand.
Nephrol Dial Transplant. 2008 Sep;23(9):3017-23. doi: 10.1093/ndt/gfn185. Epub 2008 Apr 11.
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-beta1, TNF-alpha and IL-10) and outcomes after renal transplantation.
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.
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-beta1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0-2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-beta1 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 compared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9-1.6).
Pooled results to date suggest possible association between both the TGF-beta1 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.
细胞因子基因多态性与肾移植后不良结局相关，如慢性移植肾肾病（CAN）、移植排斥反应（GR）和移植失败（GF），但这些多态性的影响仍存在争议。因此，我们进行了一项系统评价，尽可能纳入个体患者数据（IPD），以确定细胞因子多态性（转化生长因子-β1、肿瘤坏死因子-α和白细胞介素-10）与肾移植后结局之间的关联。
五名研究者愿意参与并提供了IPD。感兴趣的结局为GF、GR和CAN。至少出现其中之一的受试者被分类为结局不良。评估基因效应的异质性。应用多因素logistic回归评估基因效应，并对临床变量如HLA配型和年龄进行校正。
1087名受试者纳入IPD荟萃分析。汇总结果显示无证据表明存在异质性，且表明决定不良结局的最强变量是HLA错配（≥3个HLA-A、-B、-DR错配者与<3个错配者相比，OR = 1.6 - 1.8）和年龄（45岁及以上者，OR = 1.2 - 1.4）。转化生长因子-β1 c10多态性提供了关于不良结局风险的增量信息（TC基因型与TT基因型相比，OR = 1.5，P = 0.034，95%CI：1.0 - 2.2）。推断了转化生长因子-β1在c10和c25处的单倍型，C-C单倍型是不良结局的标志物（OR = 1.3，P = 0.177，95%CI：1.0 - 2.3）。白细胞介素-10基因在-1082、-819、-592处的三个多态性彼此处于强连锁不平衡状态（相关系数：0.6 - 1），这三个位点之间推断的单倍型显示出一定关联，与GCC相比，ACC增加了不良事件的风险（OR = 1.3，P = 0.044，95%CI：0.9 - 1.6）。
迄今为止的汇总结果表明，转化生长因子-β1 c10多态性和白细胞介素-10的一个3-SNP单倍型与肾移植不良结局之间可能存在关联，但这需要在更大规模的研究中得到证实。
