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Regenerative Medicine

A candidate gene approach of the calcineurin pathway to identify variants associated with clinical outcomes in renal transplantation

    Lucie Pouché

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    ,
    Matthias Koitka

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    ,
    Jana Stojanova

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    Laboratory of Chemical Carcinogenesis & Pharmacogenetics, University of Chile, Santiago, Chile

    ,
    Jean-Baptiste Woillard

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    ,
    Caroline Monchaud

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    ,
    Claire Villeneuve

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    ,
    Marie Essig

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    CHU Limoges, Department of Nephrology, Dialysis & Transplantation, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    ,
    Julie Abraham

    CHU Limoges, Department of Clinical Hematology, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    ,
    Yannick Le Meur

    CHU Brest, Hôpital Cavale Blanche, Department of Nephrology, F-29609 Brest, France

    ,
    Jean-Phillippe Rerolle

    CHU Limoges, Department of Nephrology, Dialysis & Transplantation, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    ,
    Nassim Kamar

    CHU Toulouse Rangueil, Department of Nephrology & Organ Transplantation, F-31000 Toulouse, France

    INSERM, U1043, Structure Fédérative de Recherche Bio-Médicale de Toulouse (SFR-BMT), Centre Hospitalier Universitaire (CHU) Purpan, Toulouse, France

    Université Paul Sabatier, 118 route de Narbonne, F-31062 Toulouse, France

    ,
    Lionel Rostaing

    CHU Toulouse Rangueil, Department of Nephrology & Organ Transplantation, F-31000 Toulouse, France

    INSERM, U1043, Structure Fédérative de Recherche Bio-Médicale de Toulouse (SFR-BMT), Centre Hospitalier Universitaire (CHU) Purpan, Toulouse, France

    Université Paul Sabatier, 118 route de Narbonne, F-31062 Toulouse, France

    ,
    Pierre Merville

    CHU Bordeaux, Department of Nephrology, Transplantation, Dialysis, F-33000 Bordeaux, France

    ,
    Peggy Gandia

    CHU Toulouse, Laboratory of Pharmacokinetics & Clinical Toxicology, F-31000 Toulouse, France

    ,
    Stephane Bouchet

    CHU Bordeaux, Department of Clinical Pharmacology & Toxicology, F-33000 Bordeaux, France

    ,
    Britt-Sabina Petersen

    Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Germany

    ,
    Pierre Marquet

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    &
    Nicolas Picard

    *Author for correspondence:

    E-mail Address: nicolas.picard@unilim.fr

    Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France

    CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France

    Published Online:https://doi.org/10.2217/pgs.15.181

    Aim: To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation. Materials & methods: Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation. Results: Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor–recipient Cytomegalovirus mismatch was the only variable associated with serious infection. Conclusion: This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Rusnak F, Mertz P. Calcineurin: form and function. Physiol. Rev. 80(4), 1483–1521 (2000).
    • 2 Barbarino JM, Staatz CE, Venkataramanan R et al.. PharmGKB summary: cyclosporine and tacrolimus pathways. Pharmacogenet. Genomics 23(10), 563–585 (2013).
    • 3 Böhler T, Nolting J, Kamar N et al. Validation of immunological biomarkers for the pharmacodynamic monitoring of immunosuppressive drugs in humans. Ther. Drug Monit. 29(1), 77–86 (2007).
    • 4 Noceti OM, Woillard J-B, Boumediene A et al. Tacrolimus pharmacodynamics and pharmacogenetics along the calcineurin pathway in human lymphocytes. Clin. Chem. 60(10), 1336–1345 (2014).
    • 5 Picard N, Marquet P. The influence of pharmacogenetics and cofactors on clinical outcomes in kidney transplantation. Expert Opin. Drug Metab. Toxicol. 7(6), 731–743 (2011).
    • 6 Moscoso-Solorzano GT, Ortega F, Rodríguez I et al. A search for cyclophilin-A gene variants in cyclosporine A-treated renal transplanted patients. Clin. Transplant. 22(6), 722–729 (2008).• A report associating PPIA rs8177826 with nephrotoxicity in renal transplant recipients.
    • 7 Seyhun Y, Mytilineos J, Turkmen A et al. Influence of cytokine gene polymorphisms on graft rejection in Turkish patients with renal transplants from living related donors. Transplant. Proc. 44(6), 1670–1678 (2012).• A study showing that IL2 rs2069763 associates with acute rejection in renal transplant recipients.
    • 8 Morgun A, Shulzhenko N, Rampim GF et al. Interleukin-2 gene polymorphism is associated with renal but not cardiac transplant outcome. Transplant. Proc. 35(4), 1344–1345 (2003).• A higher frequency of IL2 rs2069762 TT genotype was found in renal transplant recipients experiencing at least one biopsy proven acute rejection episode.
    • 9 Rits MAN, van Dort KA, Kootstra NA. Polymorphisms in the regulatory region of the cyclophilin A gene influence the susceptibility for HIV-1 infection. PLoS ONE 3(12), e3975 (2008).
    • 10 An P, Wang LH, Hutcheson-Dilks H et al. Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS. PLoS Pathog. 3(6), e88 (2007).
    • 11 Palacín M, Rodríguez I, García-Castro M et al. A search for cyclophilin-A gene (PPIA) variation and its contribution to the risk of atherosclerosis and myocardial infarction. Int. J. Immunogenet. 35(2), 159–164 (2008).
    • 12 Le Meur Y, Büchler M, Thierry A et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am. J. Transplant. 7(11), 2496–2503 (2007).
    • 13 Le Meur Y, Thierry A, Glowacki F et al. Early steroid withdrawal and optimization of mycophenolic acid exposure in kidney transplant recipients receiving mycophenolate mofetil. Transplantation 92(11), 1244–1251 (2011).
    • 14 Medical Dictionary for Regulatory Activities. www.meddra.org.
    • 15 Untergasser A, Nijveen H, Rao X, Bisseling T, Geurts R, Leunissen JAM. Primer3Plus, an enhanced web interface to Primer3. Nucleic Acids Res. 35, W71–W74 (2007).
    • 16 Chiocco MJ, Zhu X, Walther D et al. Fine mapping of calcineurin (PPP3CA) gene reveals novel alternative splicing patterns, association of 5′UTR trinucleotide repeat with addiction vulnerability, and differential isoform expression in Alzheimer's disease. Subst. Use Misuse 45(11), 1809–1826 (2010).
    • 17 Tang W, Arnett DK, Devereux RB et al. Identification of a novel 5-base pair deletion in calcineurin B (PPP3R1) promoter region and its association with left ventricular hypertrophy. Am. Heart J. 150(4), 845–851 (2005).
    • 18 Ahmetov II, Williams AG, Popov DV et al. The combined impact of metabolic gene polymorphisms on elite endurance athlete status and related phenotypes. Hum. Genet. 126(6), 751–761 (2009).
    • 19 Cruchaga C, Kauwe JSK, Mayo K et al. SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer's disease. PLoS Genet. 6(9), e1001101 (2010).
    • 20 Zhao D, Qiu G-X, Wang Y-P. Is calmodulin 1 gene/estrogen receptor-alpha gene polymorphisms correlated with double curve pattern of adolescent idiopathic scoliosis? Zhonghua Yi Xue Za Zhi 88(35), 2452–2456 (2008).
    • 21 Mototani H, Mabuchi A, Saito S et al. A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese. Hum. Mol. Genet. 14(8), 1009–1017 (2005).
    • 22 Zhuang Q, Wu Z, Qiu G. Is polymorphism of CALM1 gene or growth hormone receptor gene associated with susceptibility to adolescent idiopathic scoliosis? Zhonghua Yi Xue Za Zhi 87(31), 2198–2202 (2007).
    • 23 Hoffmann SC, Stanley EM, Darrin Cox E et al. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation 72(8), 1444–1450 (2001).
    • 24 Hussain SK, Madeleine MM, Johnson LG et al. Cervical and vulvar cancer risk in relation to the joint effects of cigarette smoking and genetic variation in interleukin 2. Cancer Epidemiol. Biomark. 17(7), 1790–1799 (2008).
    • 25 Satoh S, Saito M, Inoue K, Miura M, Komatsuda A, Habuchi T. Association of cytokine polymorphisms with subclinical progressive chronic allograft nephropathy in Japanese renal transplant recipients: preliminary study. Int. J. Urol. 14(11), 990–994 (2007).
    • 26 Oetting WS, Schladt DP, Leduc RE et al. Validation of single nucleotide polymorphisms associated with acute rejection in kidney transplant recipients using a large multi-center cohort. Transpl. Int. 24(12), 1231–1238 (2011).
    • 27 Yucesoy B, Johnson VJ, Fluharty K et al. Influence of cytokine gene variations on immunization to childhood vaccines. Vaccine 27(50), 6991–6997 (2009).
    • 28 Dhiman N, Ovsyannikova IG, Vierkant RA, Pankratz VS, Jacobson RM, Poland GA. Associations between cytokine/cytokine receptor single nucleotide polymorphisms and humoral immunity to measles, mumps and rubella in a Somali population. Tissue Antigens 72(3), 211–220 (2008).
    • 29 van Heel DA, Franke L, Hunt KA et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat. Genet. 39(7), 827–829 (2007).
    • 30 Márquez A, Orozco G, Martínez A et al. Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease. Am. J. Gastroenterol. 104(8), 1968–1975 (2009).
    • 31 Hollis-Moffatt JE, Chen-Xu M, Topless R et al. Only one independent genetic association with rheumatoid arthritis within the KIAA1109–TENR–IL2–IL21 locus in Caucasian sample sets: confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance. Arthritis Res. Ther. 12(3), R116 (2010).
    • 32 Zhernakova A, Alizadeh BZ, Bevova M et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of Type 1 diabetes point to a general risk locus for autoimmune diseases. Am. J. Hum. Genet. 81(6), 1284–1288 (2007).
    • 33 Fichna M, Zurawek M, Fichna P, Ziółkowska-Suchanek I, Januszkiewicz D, Nowak J. Polymorphic variant at the IL2 region is associated with Type 1 diabetes and may affect serum levels of interleukin-2. Mol. Biol. Rep. 40(12), 6957–6963 (2013).
    • 34 International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A et al. Risk alleles for multiple sclerosis identified by a genome-wide study. N. Engl. J. Med. 357(9), 851–862 (2007).
    • 35 D'Netto MJ, Ward H, Morrison KM et al. Risk alleles for multiple sclerosis in multiplex families. Neurology 72(23), 1984–1988 (2009).
    • 36 Kurreeman FAS, Daha NA, Chang M et al. Association of IL2RA and IL2RB with rheumatoid arthritis: a replication study in a Dutch population. Ann. Rheum. Dis. 68(11), 1789–1790 (2009).
    • 37 Alcina A, Fedetz M, Ndagire D et al. IL2RA/CD25 gene polymorphisms: uneven association with multiple sclerosis (MS) and Type 1 diabetes (T1D). PLoS ONE 4(1), e4137 (2009).
    • 38 Srivastava B, Mells GF, Cordell HJ et al. Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis. Scand. J. Gastroenterol. 47(7), 820–826 (2012).
    • 39 Schmied MC, Zehetmayer S, Reindl M et al. Replication study of multiple sclerosis (MS) susceptibility alleles and correlation of DNA-variants with disease features in a cohort of Austrian MS patients. Neurogenetics 13(2), 181–187 (2012).
    • 40 Carr EJ, Clatworthy MR, Lowe CE et al. Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis. BMC Med. Genet. 10, 22 (2009).
    • 41 Lowe CE, Cooper JD, Brusko T et al. Large-scale genetic fine mapping and genotype–phenotype associations implicate polymorphism in the IL2RA region in Type 1 diabetes. Nat. Genet. 39(9), 1074–1082 (2007).
    • 42 Qu H-Q, Bradfield JP, Bélisle A et al. The Type I diabetes association of the IL2RA locus. Genes Immun. 10(Suppl. 1), S42–S48 (2009).
    • 43 Qu H-Q, Montpetit A, Ge B, Hudson TJ, Polychronakos C. Toward further mapping of the association between the IL2RA locus and Type 1 diabetes. Diabetes 56(4), 1174–1176 (2007).
    • 44 Redler S, Albert F, Brockschmidt FF et al. Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata. Br. J. Dermatol. 167(6), 1360–1365 (2012).
    • 45 Ban Y, Tozaki T, Taniyama M et al. Association of the protein tyrosine phosphatase nonreceptor 22 haplotypes with autoimmune thyroid disease in the Japanese population. Thyroid 20(8), 893–899 (2010).
    • 46 Babron M-C, Perdry H, Handel AE et al. Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis. Eur. J. Hum. Genet. 20(3), 321–325 (2012).
    • 47 Aslibekyan S, Kabagambe EK, Irvin MR et al. A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network. Pharmacogenet. Genomics 22(3), 191–197 (2012).
    • 48 Perera D, Stankovich J, Butzkueven H et al. Fine mapping of multiple sclerosis susceptibility genes provides evidence of allelic heterogeneity at the IL2RA locus. J. Neuroimmunol. 211(1–2), 105–109 (2009).
    • 49 R Foundation for Statistical Computing. www.r-project.org.
    • 50 Paramesh AS, Zhang R, Baber J et al. The effect of HLA mismatch on highly sensitized renal allograft recipients. Clin. Transplant. 24(6), E247–E252 (2010).
    • 51 Abdi ZD, Prémaud A, Essig M et al. Exposure to mycophenolic acid better predicts immunosuppressive efficacy than exposure to calcineurin inhibitors in renal transplant patients. Clin. Pharmacol. Ther. 96(4), 508–515 (2014).
    • 52 Pallardó Mateu LM, Sancho Calabuig A, Capdevila Plaza L, Franco Esteve A. Acute rejection and late renal transplant failure: risk factors and prognosis. Nephrol. Dial. Transplant. 19(Suppl. 3), iii38–iii42 (2004).
    • 53 Pouché L, Avcu K, Esperón P, Noceti OM, Marquet P, Picard N. Genetic databases and their pitfalls: an example related to pharmacogenetics. Ther Drug Monit. 35(5), 713–714 (2013).
    • 54 Pouché L, Stojanova J, Marquet P, Picard N. New challenges and promises in solid organ transplantation pharmacogenetics: the genetic variability of proteins involved in the pharmacodynamics of immunosuppressive drugs. Pharmacogenomics (2016) (Epub ahead of print).•• A comprehensive review of candidates genes of the calcineurin pathway with reports of previous associations with different phenotypes and highlights on the most promising candidates for pharmacogenetic studies in solid organ transplantation.
    • 55 Ekberg H, Tedesco-Silva H, Demirbas A et al. ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N. Engl. J. Med. 357(25), 2562–2575 (2007).
    • 56 Picard N, Bergan S, Marquet P et al. Pharmacogenetic biomarkers predictive of the pharmacokinetics and pharmacodynamics of immunosuppressive drugs. Ther. Drug Monit. PMID: 26469711 (2015) (Epub ahead of print).
    • 57 Lefaucheur C, Nochy D, Hill GS et al. Determinants of poor graft outcome in patients with antibody-mediated acute rejection. Am. J. Transplant. 7(4), 832–841 (2007).
    • 58 George S, Turner D, Reynard M et al. Significance of cytokine gene polymorphism in renal transplantation. Transplant. Proc. 33(1–2), 483–484 (2001).
    • 59 Hoffmann S, Park J, Jacobson LM et al. Donor genomics influence graft events: the effect of donor polymorphisms on acute rejection and chronic allograft nephropathy. Kidney Int. 66(4), 1686–1693 (2004).
    • 60 Manchanda PK, Mittal RD. Analysis of cytokine gene polymorphisms in recipient's matched with living donors on acute rejection after renal transplantation. Mol. Cell. Biochem. 311(1–2), 57–65 (2008).
    • 61 Grinyó J, Vanrenterghem Y, Nashan B et al. Association of four DNA polymorphisms with acute rejection after kidney transplantation. Transpl. Int. 21(9), 879–891 (2008).
    • 62 Karimi MH, Daneshmandi S, Pourfathollah AA et al. A study of the impact of cytokine gene polymorphism in acute rejection of renal transplant recipients. Mol. Biol. Rep. 39(1), 509–515 (2012).
    • 63 Chen Z, Bouamar R, Van Schaik RHN et al. Genetic polymorphisms in IL-2, IL-10, TGF-β1, and IL-2RB and acute rejection in renal transplant patients. Clin. Transplant. 28(6), 649–655 (2014).
    • 64 Moore J, McKnight AJ, Döhler B et al. Donor ABCB1 variant associates with increased risk for kidney allograft failure. J. Am. Soc. Nephrol. 23(11), 1891–1899 (2012).
    • 65 Naim I. Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. Am. J. Nephrol. 37(6), 602–612 (2013).
    • 66 Naesens M, Kuypers DRJ, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin. J. Am. Soc. Nephrol. 4(2), 481–508 (2009).
    • 67 Sibbring JS, Sharma A, McDicken IW, Sells RA, Christmas SE. Localization of C-X-C and C-C chemokines to renal tubular epithelial cells in human kidney transplants is not confined to acute cellular rejection. Transpl. Immunol. 6(4), 203–208 (1998).
    • 68 Hoffmann S, Park J, Jacobson LM et al. Donor genomics influence graft events: the effect of donor polymorphisms on acute rejection and chronic allograft nephropathy. Kidney Int. 66(4), 1686–1693 (2004).
    • 69 Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am. J. Transplant. 4(4), 583–595 (2004).