Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium.
Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium.
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DOI：
10.1097/tp.0b013e318200e991
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发表时间：
2011-02-15
期刊：
影响因子：
6.2
通讯作者：
DeKAF Investigators
中科院分区：
文献类型：
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作者：
Jacobson PA;Oetting WS;Brearley AM;Leduc R;Guan W;Schladt D;Matas AJ;Lamba V;Julian BA;Mannon RB;Israni A;DeKAF Investigators
CYP 4503 A5 *1基因型与他克莫司浓度较低相关。虽然其作用很重要，但它不能完全解释他克莫司浓度的变异性，并且相对于非洲裔美国人（AA），高加索人的次要等位基因频率相对较低。我们通过一个7中心联盟，在一个大型的、种族多样的（144个AA和551个非AA）成人肾移植人群中，使用定制的单核苷酸多态性芯片（2,722个变异体）研究了移植后前6个月剂量标准化他克莫司谷值（n=12,277）的临床和受体遗传相关性。在6个月的研究中，AA的中位（四分位距）谷值始终低于非AA，6.2（4.4-8.4）vs 8.3（6.4-10.4）ng/mL（p<0.0001），尽管每日剂量高60%，8 vs 5 mg（p<0.0001）。尽管初始剂量相似，但移植后第1周他克莫司谷浓度中位数在AA中[2.1（1.2-3.5）]特别低于非AA [5.0（3.1-8.2）ng/mL]（p<0.0001）。在单变量分析中，CYP 3A 5 *3（rs776746）是与谷值相关的最高变量（p=2.4x10−33）。在对CYP 3A 5 *3、临床因素和种族进行调整后，确定了39个额外的变体（p<0.01，在FDR 20%时不显著）。在最终的多变量回归模型中，从这些变体和临床因素开始，在非AA和AA组中分别确定了7种变体和7种变体，接近第一个谷浓度。Rs776746（CYP 3A 5）、rs 2239393（COMT）和糖尿病是两个人群中唯一共同的因素。我们确定了CYP 3A 5 *3以外的变异体，这可能进一步解释他克莫司的药代动力学变异性，并证明了重要的变异体因人种而异。
The CYP4503A5*1 genotype is associated with lower tacrolimus concentrations. Although its effect is important, it incompletely explains the variability in tacrolimus concentrations and has a relatively low minor allele frequency in Caucasians relative to African Americans (AA). We studied clinical and recipient genetic correlates of dose-normalized tacrolimus troughs (n=12,277) in the first 6 months posttransplant using a customized single nucleotide polymorphism chip with 2,722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a 7-center consortium. Over the 6 month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4–8.4) vs 8.3 (6.4–10.4) ng/mL (p<0.0001), in spite of 60% higher daily doses, 8 vs 5 mg (p<0.0001). The median tacrolimus trough concentration in week one posttransplant was particularly low in AAs [2.1 (1.2–3.5)] compared to non-AAs [5.0 (3.1–8.2) ng/mL](p<0.0001) despite similar initial doses. In single variant analysis, CYP3A5*3 (rs776746) was the top variant (p=2.4x10−33) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, thirty-nine additional variants were identified (p<0.01, not significant at FDR 20%). In the final multivariant, regression models beginning with these variants and clinical factors, 7 variants were identified in the non-AA and 7 variants in the AA group towards the first trough concentrations. Rs776746 (CYP3A5), rs2239393 (COMT) and diabetes were the only factors common in both populations. We identified variants beyond CYP3A5*3 which may further explain pharmacokinetic variability of tacrolimus and demonstrated that important variants differ by race.