Grinyó Josep, Vanrenterghem Yves, Nashan Björn, Vincenti Flavio, Ekberg Henrik, Lindpaintner Klaus, Rashford Michelle, Nasmyth-Miller Clare, Voulgari Athina, Spleiss Olivia, Truman Matthew, Essioux Laurent
Department of Nephrology, Hospital de Bellvitge, University of Barcelona, Barcelona, Spain.
Transpl Int. 2008 Sep;21(9):879-91. doi: 10.1111/j.1432-2277.2008.00679.x. Epub 2008 Apr 25.
Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50-6.67]; P=0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42-8.09]; P=0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52-14.55]; P=0.007) and twice as likely in patients with at least one A allele of TNF-alpha G-308A (OR: 2.18, 95% CI [1.08-4.41]; P=0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.
肾移植结果存在很大的个体间差异，这可能是由于免疫反应介质的基因变异以及影响免疫抑制剂药效学/药代动力学的基因所致。我们在237例初发肾移植受者中检测了来自10个基因的21个多态性，这些受者参与了一项开放标签、多中心研究[环孢素避免消除严重的肾毒性（CAESAR）]，该研究采用不同的环孢素A方案和霉酚酸酯来研究肾功能和活检证实的急性排斥反应（BPAR）。选择这些基因是因其与免疫反应以及药效学/药代动力学相关，并检测其与BPAR的关联性。有4个多态性与BPAR显著相关。ABCB1 2677T等位基因使发生BPAR的几率增加两倍（OR：3.16，95%CI[1.50 - 6.67]；P = 0.003），至少存在一个IMPDH2 3757C等位基因时也是如此（OR：3.39，95%CI[1.42 - 8.09]；P = 0.006）。IL - 10 - 592A纯合子患者发生BPAR的可能性几乎高五倍（OR：4.71，95%CI[1.52 - 14.55]；P = 0.007），而TNF - α G - 308A至少有一个A等位基因的患者发生BPAR的可能性高两倍（OR：2.18，95%CI[1.08 - 4.41]；P = 0.029）。多态性之间或不同治疗方案之间没有统计学上的显著相互作用。免疫反应以及药效学/药代动力学相关基因的变异可能对理解肾移植后的急性排斥反应很重要。
