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Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.
The Pharmacogenomics Journal ( IF 2.9 ) Pub Date : 2019-04-17 , DOI: 10.1038/s41397-019-0086-0
Laneshia K Tague 1 , Derek E Byers 1 , Ramsey Hachem 1 , Daniel Kreisel 2 , Alexander S Krupnick 3 , Hrishikesh S Kulkarni 1 , Catherine Chen 4 , Howard J Huang 5 , Andrew Gelman 2
Affiliation  

Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

中文翻译:


SLCO1B3 多态性对接受霉酚酸的肺同种异体移植受者的临床结果的影响。



霉酚酸 (MPA) 代谢相关基因中的单核苷酸多态性 (SNP) 已被证明会导致不同的 MPA 暴露,但其临床效果尚不清楚。我们的目的是确定 MPA 代谢关键基因中的 S​​NP 是否影响肺移植后的结果。我们对 275 名肺移植受者进行了一项回顾性队列研究,其中 228 名接受霉酚酸治疗,对照组 47 名接受硫唑嘌呤治疗。对来自 SLCO、UGT 和 MRP2 家族的 6 个已知调节 MPA 暴露的 SNP 进行了基因分型。主要结局是一年生存率。次要结局是 3 年生存率、非最小(≥A2 或 B2)急性排斥反应和慢性肺同种异体移植功能障碍(CLAD)。统计分析包括事件时间 Kaplan-Meier 与对数秩检验和 Cox 回归模型。我们发现 SLCO1B3 SNP rs4149117 和 rs7311358 与 1 年生存率降低相关 [rs7311358 HR 7.76 (1.37-44.04),p = 0.021; rs4149117 HR 7.28 (1.27-41.78),p = 0.026],非最小急性排斥反应风险增加[rs4149117 TT334/T334G:OR 2.01 (1.06-3.81),p = 0.031; rs7311358 GG699/G699A:OR 2.18 (1.13-4.21) p = 0.019],MPA 患者的 3 年生存率较低,但硫唑嘌呤患者则不然。 SLCO1B3 SNP 的 MPA 携带者在 CLAD 诊断后生存期较短(rs4149117 p = 0.048,rs7311358 p = 0.023)。对于 MPA 患者,Cox 回归模型证明这两个 SNP 仍然是死亡的独立危险因素。我们得出的结论是,SLCO1B3 基因中功能低下的 SNP 与接受 MPA 治疗的肺移植受者急性排斥反应和同种异体移植失败的风险增加有关。
更新日期:2019-11-18
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