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CYP3A4 and GCK genetic polymorphisms are the risk factors of tacrolimus-induced new-onset diabetes after transplantation in renal transplant recipients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

We intend to investigate the association between tacrolimus-induced new-onset diabetes after transplantation (NODAT) and polymorphisms of CYP3A4, CYP3A5, ATP-binding cassette transporter sub-family C member 8 (ABCC8), and glucokinase (GCK) in renal transplant recipients.

Methods

Polymorphisms of CYP3A4 *18B, CYP3A5 *3, ABCC8 T-3C, and GCK G-30A were genotyped in 169 renal transplant recipients. Trough concentrations of tacrolimus were detected by an ELISA kit. The relative materials were collected in all patients and volunteers. The association of NODAT and polymorphisms was analyzed.

Results

CYP3A4 *18B and GCK G-30A were related to NODAT (p < 0.05). The lower concentration/dose or fasting serum glucose was in CYP3A4 *1/*1 carriers than that in *18B/*18B carriers in all the renal transplant recipients (p < 0.05), respectively. Genotype of ABCC8 T-3C was associated with fasting serum glucose in both NODAT and non-NODAT patients (p < 0.05). Furthermore, family history of DM (OR = 3.734, p = 0.002), concentration/dose above 70 ([ng/mL]/[mg/kg]) (OR = 2.154, p = 0.034) and GCK G-30A (OR = 2.272, p = 0.026) were independently correlated with the incidence of NODAT in logistic regression.

Conclusions

The polymorphisms of CYP3A4 *18B and GCK G-30A were related to NODAT induced by tacrolimus.

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References

  1. Lim WH, Wong G, Pilmore HL, McDonald SP, Chadban SJ (2017) Long-term outcomes of kidney transplantation in people with type 2 diabetes: a population cohort study. Lancet Diabetes Endocrinol 5(1):26–33. https://doi.org/10.1016/S2213-8587(16)30317-5

    Article  PubMed  Google Scholar 

  2. Davidson J, Wilkinson A, Dantal J, Dotta F, Haller H, Hernandez D, Kasiske BL, Kiberd B, Krentz A, Legendre C, Marchetti P, Markell M, van der Woude FJ, Wheeler DC (2003) New-onset diabetes after transplantation: 2003 international consensus guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003. Transplantation 75(10 Suppl):SS3–S24. https://doi.org/10.1097/01.TP0000069952.49242.3E

    PubMed  Google Scholar 

  3. Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC (2002) Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 25(3):583–592

    Article  PubMed  Google Scholar 

  4. Prokai A, Fekete A, Pasti K, Rusai K, Banki NF, Reusz G, Szabo AJ (2012) The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 13(1):81–91. https://doi.org/10.1111/j.1399-5448.2011.00782.x

    Article  CAS  PubMed  Google Scholar 

  5. Heisel O, Heisel R, Balshaw R, Keown P (2004) New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 4(4):583–595. https://doi.org/10.1046/j.1600-6143.2003.00372.x

    Article  PubMed  Google Scholar 

  6. Baron PW, Infante S, Peters R, Tilahun J, Weissman J, Delgado L, Kore AH, Beeson WL, de Vera ME (2017) Post-transplant diabetes mellitus after kidney transplant in Hispanics and Caucasians treated with tacrolimus-based immunosuppression. Ann Transplant 22:309–314

    Article  PubMed  Google Scholar 

  7. Tamashiro EY, Felipe CR, Genvigir FDV, Rodrigues AC, Campos AB, Hirata RDC, Tedesco-Silva H, Medina-Pestana JO (2017) Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients. Drug Metab Pers Ther 32(2):89–95. https://doi.org/10.1515/dmpt-2016-0036

    CAS  PubMed  Google Scholar 

  8. Kuypers DR, de Loor H, Naesens M, Coopmans T, de Jonge H (2014) Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients. Pharmacogenet Genomics 24(12):597–606. https://doi.org/10.1097/FPC.0000000000000095

    Article  CAS  PubMed  Google Scholar 

  9. Penfornis A, Kury-Paulin S (2006) Immunosuppressive drug-induced diabetes. Diabetes Metab 32(5 Pt 2):539–546

    Article  CAS  PubMed  Google Scholar 

  10. Niu X, Yang H, Zhang HY, Li NJ, Qi XM, Chang Y, Chang Z, Zhang Y (2005) Study on association between gestational diabetes mellitus and sulfonylurea receptor-1 gene polymorphism. Chin J Obstetric Gynecol 40(3):159–163

    Google Scholar 

  11. Basu A, Basu R, Shah P, Vella A, Johnson CM, Jensen M, Nair KS, Schwenk WF, Rizza RA (2001) Type 2 diabetes impairs splanchnic uptake of glucose but does not alter intestinal glucose absorption during enteral glucose feeding: additional evidence for a defect in hepatic glucokinase activity. Diabetes 50(6):1351–1362

    Article  CAS  PubMed  Google Scholar 

  12. Haeusler RA, Camastra S, Astiarraga B, Nannipieri M, Anselmino M, Ferrannini E (2015) Decreased expression of hepatic glucokinase in type 2 diabetes. Mol Metab 4(3):222–226. https://doi.org/10.1016/j.molmet.2014.12.007

    Article  CAS  PubMed  Google Scholar 

  13. Elens L, Sombogaard F, Hesselink DA, van Schaik RH, van Gelder T (2013) Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor-alpha are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet Genomics 23(12):649–657. https://doi.org/10.1097/FPC.0000000000000001

    Article  CAS  PubMed  Google Scholar 

  14. Regelmann MO, Goldis M, Arnon R (2015) New-onset diabetes mellitus after pediatric liver transplantation. Pediatr Transplant 19(5):452–459. https://doi.org/10.1111/petr.12523

    Article  PubMed  Google Scholar 

  15. Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y (2007) CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther 82(6):711–725. https://doi.org/10.1038/sj.clpt.6100216

    Article  CAS  PubMed  Google Scholar 

  16. Li JL, Liu S, Fu Q, Zhang Y, Wang XD, Liu XM, Liu LS, Wang CX, Huang M (2015) Interactive effects of CYP3A4, CYP3A5, MDR1 and NR1I2 polymorphisms on tracrolimus trough concentrations in early postrenal transplant recipients. Pharmacogenomics 16(12):1355–1365. https://doi.org/10.2217/pgs.15.78

    Article  CAS  PubMed  Google Scholar 

  17. Zuo XC, Ng CM, Barrett JS, Luo AJ, Zhang BK, Deng CH, Xi LY, Cheng K, Ming YZ, Yang GP, Pei Q, Zhu LJ, Yuan H, Liao HQ, Ding JJ, Wu D, Zhou YN, Jing NN, Huang ZJ (2013) Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis. Pharmacogenet Genomics 23(5):251–261. https://doi.org/10.1097/FPC.0b013e32835fcbb6

    Article  CAS  PubMed  Google Scholar 

  18. Liu S, Shi X, Tian X, Zhang X, Sun Z, Miao L (2017) Effect of CYP3A4 *1G and CYP3A5 *3 polymorphisms on pharmacokinetics and pharmacodynamics of Ticagrelor in healthy Chinese subjects. Front Pharmacol 8:176. https://doi.org/10.3389/fphar.2017.00176

    PubMed  PubMed Central  Google Scholar 

  19. Zhang HJ, Li DY, Zhu HJ, Fang Y, Liu TS (2017) Tacrolimus population pharmacokinetics according to CYP3A5 genotype and clinical factors in Chinese adult kidney transplant recipients. J Clin Pharm Ther 42(4):425–432. https://doi.org/10.1111/jcpt.12523

    Article  CAS  PubMed  Google Scholar 

  20. Chen P, Li J, Li J, Deng R, Fu Q, Chen J, Huang M, Chen X, Wang C (2017) Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients. J Clin Pharm Ther 42(1):93–97. https://doi.org/10.1111/jcpt.12480

    Article  CAS  PubMed  Google Scholar 

  21. Tang JT, Andrews LM, van Gelder T, Shi YY, van Schaik RH, Wang LL, Hesselink DA (2016) Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations. Expert Opin Drug Metab Toxicol 12(5):555–565. https://doi.org/10.1517/17425255.2016.1170808

    Article  CAS  PubMed  Google Scholar 

  22. Haghverdizadeh P, Sadat Haerian M, Haghverdizadeh P, Sadat Haerian B (2014) ABCC8 genetic variants and risk of diabetes mellitus. Gene 545(2):198–204. https://doi.org/10.1016/j.gene.2014.04.040

    Article  CAS  PubMed  Google Scholar 

  23. Pietrzak-Nowacka M, Safranow K, Binczak-Kuleta A, Rozanski J, Ciechanowski K, Ciechanowicz A (2012) Association of C49620T ABCC8 polymorphism with anthropometric and metabolic parameters in patients with autosomal dominant polycystic kidney disease: a preliminary study. Nefrologia 32(2):153–159. https://doi.org/10.3265/Nefrologia.pre2011.Dec.10663

    PubMed  Google Scholar 

  24. Nikolac N, Simundic AM, Saracevic A, Katalinic D (2012) ABCC8 polymorphisms are associated with triglyceride concentration in type 2 diabetics on sulfonylurea therapy. Genet Test Mol Biomarkers 16(8):924–930. https://doi.org/10.1089/gtmb.2011.0337

    Article  CAS  PubMed  Google Scholar 

  25. Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M, Hara K, Kadowaki T, Tanizawa Y, Oka Y, Iwami Y, Ohgawara H, Yamada Y, Seino Y, Yano H, Cox NJ, Seino S (2006) Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. Diabetes 55(8):2379–2386. https://doi.org/10.2337/db05-1203

    Article  CAS  PubMed  Google Scholar 

  26. He YY, Zhang R, Shao XY, Hu C, Wang CR, Lu JX, Bao YQ, Jia WP, Xiang KS (2008) Association of KCNJ11 and ABCC8 genetic polymorphisms with response to repaglinide in Chinese diabetic patients. Acta Pharmacol Sin 29(8):983–989. https://doi.org/10.1111/j.1745-7254.2008.00840.x

    Article  CAS  PubMed  Google Scholar 

  27. Han X, Cui H, Chen X, Xie W, Chang Y (2015) Association of the glucokinase gene promoter polymorphism -30G > A (rs1799884) with gestational diabetes mellitus susceptibility: a case-control study and meta-analysis. Arch Gynecol Obstet 292(2):291–298. https://doi.org/10.1007/s00404-015-3635-z

    Article  CAS  PubMed  Google Scholar 

  28. Wang H, Liu L, Zhao J, Cui G, Chen C, Ding H, Wang DW (2013) Large scale meta-analyses of fasting plasma glucose raising variants in GCK, GCKR, MTNR1B and G6PC2 and their impacts on type 2 diabetes mellitus risk. PLoS One 8(6):e67665. https://doi.org/10.1371/journal.pone.0067665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Papadimitriou DT, Willems PJ, Bothou C, Karpathios T, Papadimitriou A (2015) A novel heterozygous mutation in the glucokinase gene is responsible for an early-onset mild form of maturity-onset diabetes of the young, type 2. Diabetes Metab 41(4):342–343. https://doi.org/10.1016/j.diabet.2015.03.009

    Article  CAS  PubMed  Google Scholar 

  30. Holmkvist J, Almgren P, Lyssenko V, Lindgren CM, Eriksson KF, Isomaa B, Tuomi T, Nilsson P, Groop L (2008) Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes. Diabetes 57(6):1738–1744. https://doi.org/10.2337/db06-1464

    Article  CAS  PubMed  Google Scholar 

  31. Brayne C, Gao L, Matthews F (2005) Challenges in the epidemiological investigation of the relationships between physical activity, obesity, diabetes, dementia and depression. Neurobiol Aging 26(Suppl 1):6–10. https://doi.org/10.1016/j.neurobiolaging.2005.09.030

    Article  PubMed  Google Scholar 

  32. Yan X, Xia H, Li H, Deng X, Yang L, Zhao S, Zou J, Luo Y, Cao S (2017) Diabetes in Shenzhen, China: epidemiological investigation and health care challenges. J Glob Health 7(1):011102. https://doi.org/10.7189/jogh.07.011102

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lipscombe LL, Hux JE (2007) Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a population-based study. Lancet 369(9563):750–756. https://doi.org/10.1016/s0140-6736(07)60361-4

    Article  PubMed  Google Scholar 

  34. Zghebi SS, Steinke DT, Carr MJ, Rutter MK, Emsley RA, Ashcroft DM (2017) Examining trends in type 2 diabetes incidence, prevalence and mortality in the UK between 2004 and 2014. Diabetes Obes Metab 19(11):1537–1545. https://doi.org/10.1111/dom.12964

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Scientific Foundation of Fuzhou General Hospital of PLA[200745], China.

Author information

Author notes

  1. Daohua Shi, Tiancheng Xie and Jie Deng contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, 18 Daoshan Road, Fuzhou, Fujian, China

    Daohua Shi, Tiancheng Xie, Jie Deng & Peiguang Niu

  2. Department of Urology, Fuzhou General Hospital of PLA, Fuzhou, Fujian, China

    Weizhen Wu

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  1. Daohua Shi
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Contributions

Conceived and designed the experiments: Daohua Shi, Tiancheng Xie.

Conducted the experiments: Tiancheng Xie, Jie Deng.

Performed data analysis: Jie Deng, Peiguang Niu.

Contributed reagents/materials/analysis tools: Peiguang Niu.

Wrote or contributed to the writing of the manuscript: Daohua Shi, Jie Deng.

Patient collection: Weizhen Wu.

Corresponding author

Correspondence to Daohua Shi.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the principles of 1964 Helsinki declaration. Informed consent was obtained from all individual participants included in the study.

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Cite this article

Shi, D., Xie, T., Deng, J. et al. CYP3A4 and GCK genetic polymorphisms are the risk factors of tacrolimus-induced new-onset diabetes after transplantation in renal transplant recipients. Eur J Clin Pharmacol 74, 723–729 (2018). https://doi.org/10.1007/s00228-018-2442-4

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  • DOI: https://doi.org/10.1007/s00228-018-2442-4

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