Novel polymorphisms associated with tacrolimus trough concentrations: Results from a multicenter kidney transplant consortium

Pamala A. Jacobson, William S. Oetting, Ann M. Brearley, Robert Leduc, Weihau Guan, David Schladt, Arthur J. Matas, Vishal Lamba, Bruce A. Julian, Rosalyn B. Mannon, Ajay Israni

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

Background: The CYP4503A5*1 genotype is associated with lower tacrolimus concentrations. Although its effect is important, it incompletely explains the variability in tacrolimus concentrations and has a relatively low minor allele frequency in whites relative to African Americans (AA). Methods: We studied clinical and recipient genetic correlates of dose-normalized tacrolimus troughs (n=12,277) in the first 6 months posttransplant using a customized single-nucleotide polymorphism chip with 2722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a seven-center consortium. Results: During the 6-month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4-8.4) ng/mL vs. 8.3 (6.4-10.4) ng/mL (P<0.0001), despite 60% higher daily doses, 8 (5-10) mg vs. 5 (4-7) mg (P<0.0001). The median tacrolimus trough concentration in week 1 posttransplant was particularly low in AAs (2.1 [1.2-3.5] ng/mL) compared with non-AAs (5.0 [3.1-8.2] ng/mL) (P<0.0001), despite similar initial doses. In single-variant analysis, CYP3A5*3 (rs776746) was the top variant (P=2.4×10-33) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, 35 additional variants were identified (P<0.01, not significant at false discovery rate 20%). In the final multivariant, regression models beginning with these variants and clinical factors, seven variants were identified in the non-AA and seven variants in the AA group towards the first trough concentrations. Rs776746 (CYP3A5), rs2239393 (COMT) and diabetes were the only factors common in both populations. Conclusion: We identified variants beyond CYP3A5*3, which may further explain pharmacokinetic variability of tacrolimus and demonstrated that important variants differ by race.

Original languageEnglish (US)
Pages (from-to)300-308
Number of pages9
JournalTransplantation
Volume91
Issue number3
DOIs
StatePublished - Feb 15 2011

Keywords

  • Cytochrome P450
  • Pharmacogenetics
  • Pharmacokinetics
  • Tacrolimus

Fingerprint Dive into the research topics of 'Novel polymorphisms associated with tacrolimus trough concentrations: Results from a multicenter kidney transplant consortium'. Together they form a unique fingerprint.

  • Cite this