Multigene predictors of tacrolimus exposure in kidney transplant recipients.
Multigene predictors of tacrolimus exposure in kidney transplant recipients.
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DOI：
10.2217/pgs.15.42
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发表时间：
2015-07
期刊：
影响因子：
2.1
通讯作者：
DeKAF Investigators
中科院分区：
文献类型：
--
作者：
Pulk RA;Schladt DS;Oetting WS;Guan W;Israni AK;Matas AJ;Remmel RP;Jacobson PA;DeKAF Investigators
确定CYP 3A 5 *3以外的遗传变异对他克莫司处置的影响。我们在一个大型的、种族多样的肾移植队列中研究了他克莫司谷浓度与POR*28、CYP 3A 4 *22和ABCC 2单倍型的遗传相关性（n = 2008）。携带一个或多个CYP 3A 5 *1等位基因的受试者的他克莫司谷浓度较低（p = 9.2 × 10−75）。在调整CYP 3A 5 *1和临床因素后，存在一个或两个POR*28等位基因与他克莫司谷浓度降低4.63%相关（p = 0.037）。在亚组分析中，POR*28仅在CYP 3A 5 *3/*3携带者中具有显著性（p = 0.03）。CYP 3A 4 *22变异体和ABBC 2单倍型不相关。本研究证实，CYP 3A 5 *1与他克莫司谷浓度降低相关。POR*28与他克莫司谷浓度降低相关，尽管可能通过增强CYP 3A 4酶活性产生的影响较小。CYP 3A 4 *22和ABCC 2单倍型不影响他克莫司谷浓度。
Determine the effect of the genetic variants beyond CYP3A5*3 on tacrolimus disposition. We studied genetic correlates of tacrolimus trough concentrations with POR*28, CYP3A4*22 and ABCC2 haplotypes in a large, ethnically diverse kidney transplant cohort (n = 2008). Subjects carrying one or more CYP3A5*1 alleles had lower tacrolimus trough concentrations (p = 9.2 × 10−75). The presence of one or two POR*28 alleles was associated with a 4.63% reduction in tacrolimus trough concentrations after adjusting for CYP3A5*1 and clinical factors (p = 0.037). In subset analyses, POR*28 was significant only in CYP3A5*3/*3 carriers (p = 0.03). The CYP3A4*22 variant and the ABBC2 haplotypes were not associated. This study confirmed that CYP3A5*1 was associated with lower tacrolimus trough concentrations. POR*28 was associated with decreased tacrolimus trough concentrations although the effect was small possibly through enhanced CYP3A4 enzyme activity. CYP3A4*22 and ABCC2 haplotypes did not influence tacrolimus trough concentrations.