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Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
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IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant

Mou-Ze Liu1,2,3,4, Hai-Yan He5, Yue-Li Zhang1,2

  • 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.

Acta Pharmacologica Sinica
|January 24, 2017
PubMed

Insights

Genetic variations in IL-3 and CTLA4 influence tacrolimus (TAC) dose requirements in kidney transplant patients. These findings, along with CYP3A5 and CYP3A4 gene variants, aid in personalized tacrolimus therapy.

Area of Science:

  • Pharmacogenomics
  • Transplantation Immunology
  • Clinical Pharmacology

Background:

  • Tacrolimus (TAC) exhibits variable pharmacokinetics and a narrow therapeutic window, complicating its clinical application.
  • Genetic factors are suspected to influence TAC response, but evidence remains inconclusive.

Purpose of the Study:

  • To identify novel genetic factors influencing tacrolimus dose requirements in Chinese kidney transplant recipients.
  • To investigate the association between single nucleotide polymorphisms (SNPs) and TAC dose-adjusted concentrations (C0/D).

Main Methods:

  • Genotyping of 105 pathway-related SNPs in 382 kidney transplant recipients.
  • Analysis of TAC C0/D at 7, 30, and 90 days post-operation.
  • Association analysis between specific genotypes and TAC C0/D, considering CYP3A5 expression status.

Main Results:

  • In CYP3A5 non-expressers, IL-3 rs181781 AA genotype was associated with higher TAC logC0/D at 30 and 90 days.
  • CTLA4 rs4553808 genotype showed differential effects on TAC C0/D in CYP3A5 expressers versus non-expressers at 30 days.
  • CYP3A5 and CYP3A4 SNPs (rs776746, rs2242480, rs4646437) were validated for their influence on TAC C0/D.

Conclusions:

  • Genetic polymorphisms in IL-3 rs181781 and CTLA4 rs4553808 significantly influence tacrolimus C0/D.
  • These SNPs, along with CYP3A5 and CYP3A4 variants, contribute to inter-individual variability in TAC dose requirements.
  • Incorporating these genetic markers into individualized therapy can optimize tacrolimus treatment.

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