AUTHOR=Liu Yuan , Wang Rui , Wen Peizhen , An Wenbin , Zheng Jinxin , Zhang Tao , Zhang Pengshan , Wang Haoyu , Zou Fan , Pan Hui , Fan Junwei , Peng Zhihai 

TITLE=Genetic factors underlying tacrolimus intolerance after liver transplantation

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.944442

DOI=10.3389/fimmu.2022.944442

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Tacrolimus (FK506) is the cornerstone of immunosuppression after liver transplantation (LT), however, clinically, switching from FK506 to cyclosporine (SFTC) is common in LT patients with tacrolimus intolerance. The aim of this study was to investigate the genetic risk of patients with tacrolimus intolerance.</p></sec><sec><title>Methods</title><p>A total of 114 LT patients were enrolled in this retrospective study. SNPs were genotyped using Infinium Human Exome-12 v1.2 BeadChip, and genome-wide gene expression levels were profiled using Agilent G4112F array.</p></sec><sec><title>Results</title><p>SFTC was a potential risk factor of dyslipidemia (OR=4.774[1.122-20.311], <italic>p</italic> = 0.034) and insulin resistance (IR) (OR=6.25[1.451-26.916], <italic>p</italic> = 0.014), but did not affect the survival of LT patients. Differential expression analysis showed donor <italic>CYP3A5</italic>, <italic>CYP2C9</italic>, <italic>CFTR</italic>, and <italic>GSTP1</italic>, four important pharmacogenetic genes were significantly up-regulated in the tacrolimus intolerance group. Twelve SNPs of these four genes were screened to investigate the effects on tacrolimus intolerance. Regression analysis showed donor rs4646450 (OR=3.23 [1.22-8.60] per each A allele, <italic>p</italic> = 0.01), donor rs6977165 (OR=6.44 [1.09-37.87] per each C allele, <italic>p</italic> = 0.02), and donor rs776746 (OR=3.31 [1.25-8.81] per each A allele, <italic>p</italic> = 0.01) were independent risk factors of tacrolimus intolerance.</p></sec><sec><title>Conclusions</title><p>These results suggested that SFTC was a potential risk factor for dyslipidemia and IR after LT. Besides, rs4646450, rs6977165, and rs776746 of <italic>CYP3A5</italic> might be the underlying genetic risks of tacrolimus intolerance. This might help transplant surgeons make earlier clinical decisions about the use of immunosuppression.</p></sec>