European Journal of Clinical Pharmacology

, Volume 70, Issue 8, pp 925–931

Influence of TLR4 rs1927907 locus polymorphisms on tacrolimus pharmacokinetics in the early stage after liver transplantation




The aim of this study was to assess the potential influence of single nucleotide polymorphisms (SNPs) in the TLR4 gene on tacrolimus pharmacokinetics in the early stage after liver transplantation.


A total of 96 liver transplant patients receiving tacrolimus-based immunosuppressive regimens were enrolled in this study. The SNPs of CYP3A5 rs776746 and TLR4 rs1927907 were genotyped in both donors and recipients. Trough tacrolimus concentration (ng/mL) and tacrolimus daily doses (mg/day) were recorded for the first 4 weeks post-transplantation. The tacrolimus dose-adjusted trough concentrations (C/D ratio) required to achieve target concentrations were compared among patients according to allele status for CYP3A5 rs776746 and TLR4 rs1927907 during the first 4 weeks post-transplantation.


Both donor and recipient CYP3A5 rs776746 allele A and donor TLR4 rs1927907 allele A were associated with a lower C/D ratio during the early stage after transplantation. The difference was even more striking in patients with both the CYP3A5 and TLR4 genotypes. With increasing numbers of genotype AA/AG, patients were found to have increasingly lower tacrolimus C/D ratios at all time points between post-transplantation weeks 1 and 4.


Collectively, donor TLR4 rs1927907 SNPs were closely associated with tacrolimus elimination in our Chinese Han patient population. The combination of the donor TLR4 rs1927907 SNP and both donor and recipient CYP3A5 rs776746 SNP might have a greater effect on tacrolimus elimination than each SNP separately. Screening for these SNPs prior to liver transplantation might be useful for determining adequate initial daily doses of immunosuppressive agents and achieving the desired immunosuppressive effect.


CYP3A5 Toll-like receptor 4 Single nucleotide polymorphism Tacrolimus elimination Liver transplantation 


  1. 1.
    Picard N, Marquet P (2011) The influence of pharmacogenetics and cofactors on clinical outcomes in kidney transplantation. Expert Opin Drug Metab Toxicol 7(6):731–743PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Wallemacq P, Armstrong VW, Brunet M, Haufroid V, Holt DW, Johnston A, Kuypers D, Le Meur Y, Marquet P, Oellerich M, Thervet E, Toenshoff B, Undre N, Weber LT, Westley IS, Mourad M (2009) Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit 31(2):139–152CrossRefPubMedGoogle Scholar
  3. 3.
    Tang HL, Xie HG, Yao Y, Hu YF (2011) Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers. Pharmacogenet Genomics 21(11):713–720CrossRefPubMedGoogle Scholar
  4. 4.
    Wang L, McLeod HL, Weinshilboum RM (2011) Genomics and drug response. N Engl J Med 364(12):1144–1153PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Jacobson PA, Oetting WS, Brearley AM, Leduc R, Guan W, Schladt D, Matas AJ, Lamba V, Julian BA, Mannon RB, Israni A (2011) Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation 91(3):300–308PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Zhang X, Wang Z, Fan J, Liu G, Peng Z (2011) Impact of interleukin-10 gene polymorphisms on tacrolimus dosing requirements in Chinese liver transplant patients during the early posttransplantation period. Eur J Clin Pharmacol 67(8):803–813CrossRefPubMedGoogle Scholar
  7. 7.
    Chen D, Guo F, Shi J, Zhang C, Wang Z, Fan J, Peng Z (2013) Association of hemoglobin levels, CYP3A5, and NR1I3 gene polymorphisms with tacrolimus pharmacokinetics in liver transplant patients. Drug Metab Pharmacokinet. [Epub ahead of print]Google Scholar
  8. 8.
    Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050–1059CrossRefPubMedGoogle Scholar
  9. 9.
    Schwabe RF, Seki E, Brenner DA (2006) Toll-like receptor signaling in the liver. Gastroenterology 130(6):1886–1900CrossRefPubMedGoogle Scholar
  10. 10.
    Alegre ML, Leemans J, Le Moine A, Florquin S, De Wilde V, Chong A, Goldman M (2008) The multiple facets of toll-like receptors in transplantation biology. Transplantation 86(1):1–9CrossRefPubMedGoogle Scholar
  11. 11.
    Goralski KB, Abdulla D, Sinal CJ, Arsenault A, Renton KW (2005) Toll-like receptor-4 regulation of hepatic Cyp3a11 metabolism in a mouse model of LPS-induced CNS inflammation. Am J Physiol Gastrointest Liver Physiol 289(3):G434–G443CrossRefPubMedGoogle Scholar
  12. 12.
    Ghose R, White D, Guo T, Vallejo J, Karpen SJ (2008) Regulation of hepatic drug-metabolizing enzyme genes by Toll-like receptor 4 signaling is independent of Toll-interleukin 1 receptor domain-containing adaptor protein. Drug Metab Dispos 36(1):95–101CrossRefPubMedGoogle Scholar
  13. 13.
    Gabriel S, Ziaugra L, Tabbaa D (2009) SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet Chapter 2:Unit 2. 12. doi:10.1002/0471142905.hg0212s60
  14. 14.
    Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15(2):97–98CrossRefPubMedGoogle Scholar
  15. 15.
    Kim IW, Moon YJ, Ji E, Kim KI, Han N, Kim SJ, Shin WG, Ha J, Yoon JH, Lee HS, Oh JM (2012) Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients. Eur J Clin Pharmacol 68(5):657–669CrossRefPubMedGoogle Scholar
  16. 16.
    Chen D, Fan J, Guo F, Qin S, Wang Z, Peng Z (2013) Novel single nucleotide polymorphisms in interleukin 6 affect tacrolimus metabolism in liver transplant patients. PLoS One 8(8):e73405PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Howell J, Gow P, Angus P, Visvanathan K (2014) Role of toll-like receptors in liver transplantation. Liver Transpl 20(3):270–280Google Scholar
  18. 18.
    Uhrig A, Banafsche R, Kremer M, Hegenbarth S, Hamann A, Neurath M, Gerken G, Limmer A, Knolle PA (2005) Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver. J Leukoc Biol 77(5):626–633CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang J, Wang H, Xiao Q, Liang H, Li Z, Jiang C, Wu H, Zheng Q (2009) Hyaluronic acid fragments evoke Kupffer cells via TLR4 signaling pathway. Sci China C Life Sci 52(2):147–154CrossRefPubMedGoogle Scholar
  20. 20.
    Ferwerda B, McCall MB, Verheijen K, Kullberg BJ, van der Ven AJ, Van der Meer JW, Netea MG (2008) Functional consequences of toll-like receptor 4 polymorphisms. Mol Med 14(5–6):346–352PubMedCentralPubMedGoogle Scholar
  21. 21.
    Testro AG, Visvanathan K, Skinner N, Markovska V, Crowley P, Angus PW, Gow PJ (2011) Acute allograft rejection in human liver transplant recipients is associated with signaling through toll-like receptor 4. J Gastroenterol Hepatol 26(1):155–163CrossRefPubMedGoogle Scholar
  22. 22.
    Dhillon N, Walsh L, Kruger B, Ward SC, Godbold JH, Radwan M, Schiano T, Murphy BT, Schroppel B (2010) A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation. J Hepatol 53(1):67–72CrossRefPubMedGoogle Scholar
  23. 23.
    Deng JF, Geng L, Qian YG, Li H, Wang Y, Xie HY, Feng XW, Zheng SS (2007) The role of toll-like receptors 2 and 4 in acute allograft rejection after liver transplantation. Transplant Proc 39(10):3222–3224CrossRefPubMedGoogle Scholar
  24. 24.
    Pasare C, Medzhitov R (2004) Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6(15):1382–1387CrossRefPubMedGoogle Scholar
  25. 25.
    Oetting WS, Guan W, Schladt DP, Leduc RE, Jacobson PA, Matas AJ, Chinnakotla S, Schroppel B, Murphy BT, Israni AK (2012) Donor polymorphisms of toll-like receptor 4 associated with graft failure in liver transplant recipients. Liver Transpl 18(12):1399–1405PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Zhang Q, Qian FH, Zhou LF, Wei GZ, Jin GF, Bai JL, Yin KS (2011) Polymorphisms in toll-like receptor 4 gene are associated with asthma severity but not susceptibility in a Chinese Han population. J Investig Allergol Clin Immunol 21(5):370–377PubMedGoogle Scholar
  27. 27.
    Chen YC, Yip PK, Huang YL, Sun Y, Wen LL, Chu YM, Chen TF (2012) Sequence variants of toll like receptor 4 and late-onset Alzheimer’s disease. PLoS One 7(12):e50771PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Liao P-Y, Lee KH (2010) From SNPs to functional polymorphism: the insight into biotechnology applications. Biochem Eng J 49(2):149–158CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of General Surgery, Shanghai First People’s Hospital, School of MedicineShanghai Jiao Tong UniversityShanghai CityChina

Personalised recommendations