Associations of ABCB1 3435C>T and IL-10 -1082G>A polymorphisms with long-term sirolimus dose requirements in renal transplant patients

Wai Johnn Sam, Christine E. Chamberlain, Su Jun Lee, Joyce A. Goldstein, Douglas A. Hale, Roslyn B. Mannon, Allan D. Kirk, Yuen Yi Hon

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Backgrounds. Sirolimus (SRL) absorption and metabolism are affected by p-glycoprotein-mediated transport and CYP3A enzyme activity, which are further under the influences of cytokine concentrations. This retrospective study determined the associations of adenosine triphosphate-binding cassette, subfamily B, member 1 (ABCB1) 1236C>T, 2677 G>T/A, and 3435C>T, cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) >392A>G, cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) 6986A>G and 14690G>A, interleukin (IL)-10 >1082G>A, and tumor necrosis factor (TNF) >308G>Apolymorphisms with SRL dose-adjusted, weight-normalized trough concentrations (C/D) at 7 days, and at 1, 3, 6, and 12 months after initiation of SRL. Methods: Genotypes for 86 renal transplant patients who received SRL-based maintenance immunosuppressive therapy were determined using polymerase chain reaction followed by chip-based mass spectrometry. The changes of log-transformed C/D over the days posttransplantation were analyzed using a linear mixed-effects model, with adjustments for body mass index and weight-normalized doses of tacrolimus, prednisone, clotrimazole, and statins. Results: ABCB1 3435C>T and IL-10 >1082G>A were significantly associated with log C/D (P=0.0016 and 0.0394, respectively). Mean SRL C/D was 48% higher in patients with ABCB1 3435CT/TT genotype than those with 3435CC genotype, and was 24% higher in IL-10 >1082GG compared with >1082AG/AA. Conclusions. ABCB1 3435C>T and IL-10>1082G>A were significantly associated with long-term SRL dose requirements. Genetics can play a significant role in SRL dosing and may be useful in therapeutic monitoring of SRL in renal transplantation. Future replication studies are needed to confirm these associations.

Original languageEnglish (US)
Pages (from-to)1342-1347
Number of pages6
JournalTransplantation
Volume92
Issue number12
DOIs
StatePublished - Dec 27 2011

Keywords

  • ABCB1
  • CYP3A5
  • Pharmacogenetics
  • Pharmacokinetics
  • Sirolimus

ASJC Scopus subject areas

  • Transplantation

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