Genomewide association study identifies a novel variant associated with tacrolimus trough concentration in Chinese renal transplant recipients. Issue 11 (28th August 2022)

• Record Type: Journal Article
• Authors: Yang, Siyao; Jiang, Haixia; Li, Chengcheng; Lu, Huijie; Li, Chuanjiang; Ye, Demei; Qi, Huana; Xu, Wenbin; Bao, Xiaojie; Maseko, Nicola; Zhang, Siqi; Shao, Ruifan; Li, Liang
• Is Part Of: Clinical and translational science. Volume 15:Issue 11(2022)
• Page Start: 2640
• Page End: 2651
• Publication Date: 2022-08-28
• Subjects: Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; 616.027
• DOI: 10.1111/cts.13388
• Languages: English
• ISSNs: 1752-8054

Abstract

Abstract: 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 0 / 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 −8 ) were located on chromosome 7, including CYP3A5*3 . LD, conditional association analysis, and one‐way ANOVA showed that rs75125371 T > C independently influenced TAC log( C 0 / 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 −5 ) and HepaRG cells ( p = 0.0097). A model inclusive of age, sex, hematocrit, CYP3A5*3, and rs75125371 explained 37.34% variance in TAC C 0 . These results suggest that rs75125371 T > C is a functional and population‐specific variant affecting TAC C 0 in Chinese renal transplant recipients.