Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
Department of Laboratory Medicine, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Clin Transl Sci. 2022 Nov;15(11):2640-2651. doi: 10.1111/cts.13388. Epub 2022 Aug 28.
Tacrolimus (TAC) is an immunosuppressant widely used in kidney transplantation. TAC displays considerable interindividual variability in pharmacokinetics (PKs). Genetic and clinical factors play important roles in TAC PKs. We enrolled a total of 251 Chinese renal transplant recipients and conducted a genomewide association study (GWAS), linkage disequilibrium (LD), and one-way analysis of variance (ANOVA) to find genetic variants affecting log-transformed TAC trough blood concentration/dose ratio (log[C /D]). In addition, we performed dual luciferase reporter gene assays and multivariate regression models to evaluate the effect of the genetic variants. The GWAS results showed that all 23 genomewide significant single-nucleotide polymorphisms (p < 5 × 10 ) were located on chromosome 7, including CYP3A53. LD, conditional association analysis, and one-way ANOVA showed that rs75125371 T > C independently influenced TAC log(C /D). Dual luciferase reporter gene assays indicated that rs75125371 minor allele (C) was significantly associated with increased normalized luciferase activity than the major allele (T) in the Huh7 cells (p = 1.2 × 10 ) and HepaRG cells (p = 0.0097). A model inclusive of age, sex, hematocrit, CYP3A53, and rs75125371 explained 37.34% variance in TAC C . These results suggest that rs75125371 T > C is a functional and population-specific variant affecting TAC C in Chinese renal transplant recipients.
他克莫司（TAC）是一种广泛应用于肾移植的免疫抑制剂。TAC 在药代动力学（PKs）方面表现出相当大的个体间变异性。遗传和临床因素在 TAC PKs 中起着重要作用。我们共纳入 251 例中国肾移植受者，进行全基因组关联研究（GWAS）、连锁不平衡（LD）和单因素方差分析（ANOVA），以寻找影响对数转换 TAC 谷浓度/剂量比（log[C/D]）的遗传变异。此外，我们进行了双荧光素酶报告基因检测和多元回归模型，以评估遗传变异的影响。GWAS 结果显示，所有 23 个全基因组显著单核苷酸多态性（p<5×10）均位于 7 号染色体上，包括 CYP3A53。LD、条件关联分析和单因素方差分析表明，rs75125371T>C 独立影响 TAC log(C/D)。双荧光素酶报告基因检测表明，rs75125371 次要等位基因（C）在 Huh7 细胞（p=1.2×10）和 HepaRG 细胞（p=0.0097）中的标准化荧光素酶活性显著高于主要等位基因（T）。包含年龄、性别、红细胞压积、CYP3A53 和 rs75125371 的模型解释了 TAC C 中的 37.34%的变异。这些结果表明，rs75125371T>C 是一个功能和人群特异性变异，影响中国肾移植受者的 TAC C。
