Genomewide association study identifies a novel variant associated with tacrolimus trough concentration in Chinese renal transplant recipients.

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[C₀ /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(C₀ /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 C₀ . These results suggest that rs75125371 T > C is a functional and population-specific variant affecting TAC C₀ in Chinese renal transplant recipients.

SUBMITTER: Yang S 

PROVIDER: S-EPMC9652447 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature