Abstract
Background
Idiopathic nephrotic syndrome (INS) is the most frequent type of nephrotic syndrome that occurs in children. Its response to treatment with steroids varies. The aim of this study was to analyze the correlation between steroid metabolism-related genes and the response to steroid treatment.
Methods
The patient cohort comprised 74 children with INS, of whom were 58 steroid-sensitive (SS) cases and 16 steroid-resistant (SR) cases. The genetic polymorphisms analyzed were those of the CYP3A5 gene (A6986G) and ABCB1 gene (C1236T, G2677T/A, and C3435T), and the polymorphisms between SS and SR children were compared.
Results
C1236T in ABCB1 was associated with steroid resistance in INS children [odds ratio (OR) 2.65, 95 % confidence interval (CI) 1.01–6.94; p = 0.042] The frequency of the T allele was significantly higher in SR subjects than in SS subjects (0.81 vs. 0.62, respectively). A6986G in CYP3A5 showed a trend of association, but this association did not reach statistical significance (OR 2.63, 95 % CI 0.94–7.37; p = 0.059). No significant correlation was found between treatment response and G2677T/A or C3435T in ABCB1.
Conclusions
Our results indicate that among our pediatric patients with INS the C1236T polymorphism in the ABCB1 gene was associated with steroid resistance, while the A6986G polymorphism in the CYP3A5 gene showed a trend of association, but did not reach statistical significance, requiring further analysis.
Similar content being viewed by others
References
International Study of Kidney Disease in Children (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98:561–564
McBryde KD, Kershaw DB, Smoyer WE (2001) Pediatric steroid-resistant nephrotic syndrome. Curr Probl Pediatr Adolesc Health Care 31:280–307
Tune BM, Mendoza SA (1997) Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults. J Am Soc Nephrol 8:824–832
Subramanya A, Houghton D, Watnick S (2005) Steroid-responsive idiopathic glomerular capillary endotheliosis: case report and literature review. Am J Kidney Dis 45:1090–1095
Schwab M, Eichelbaum M, Fromm MF (2003) Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 43:285–307
Stachowski J, Zanker CB, Runowski D, Zaniew M, Peszko A, Medyńska A, Zwolińska D, Rogowska-Kalisz A, Hyla-Klekot L, Szprygner K, Weglarska J, Sieniawska M, Musiał W, Maciejewski J, Baldamus CA (2000) Resistance to therapy in primary nephrotic syndrome: effect of MDR1 gene activity. Pol Merkuriusz Lek 8:218–221
Sakaeda T, Nakamura T, Okumura K (2003) Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics 4:397–410
Eichelbaum M, Fromm MF, Schwab M (2004) Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit 26:180–185
Gumus-Akay G, Rustemoglu A, Karadag A, Sunguroglu A (2008) Genotype and allele frequencies of MDR1 gene C1236T polymorphism in a Turkish population. Genet Mol Res 7:1193–1199
Xu P, Jiang ZP, Zhang BK, Tu JY, Li HD (2008) Impact of MDR1 haplotypes derived from C1236T, G2677T/A and C3435T on the pharmacokinetics of single-dose oral digoxin in healthy Chinese volunteers. Pharmacology 82:221–227
Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42
Hakkola J, Pelkonen O, Pasanen M, Raunio H (1998) Xenobiotic-metabolizing cytochrome P450 enzymes in the human feto-placental unit: role in intrauterine toxicity. Crit Rev Toxicol 28:35–72
Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389–430
Lamba JK, Lin YS, Schuetz EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54:1271–1294
Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE (2002) Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62:162–172
Finta C, Zaphiropoulos PG (2000) The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons. Gene 260:13–23
Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann CJ, Burk O, Buntefuss D, Escher S, Bishop C, Koebe HG, Brinkmann U, Klenk HP, Kleine K, Meyer UA, Wojnowski L (2001) Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 11:111–121
Beaune PH, Kremers PG, Kaminsky LS, De Graeve J, Albert A, Guengerich FP (1986) Comparison of monooxygenase activities and cytochrome P-450 isozyme concentrations in human liver microsomes. Drug Metab Dispos 14:437–442
Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS (1987) Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest 80:1029–1036
Aoyama T, Yamano S, Waxman DJ, Lapenson DP, Meyer UA, Fischer V, Tyndale R, Inaba T, Kalow W, Gelboin HV (1989) Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem 264:10388–10395
Schuetz EG, Schuetz JD, Grogan WM, Naray-Fejes-Toth A, Fejes-Toth G, Raucy J, Guzelian P, Gionela K, Watlington CO (1992) Expression of cytochrome P450 3A in amphibian, rat, and human kidney. Arch Biochem Biophys 294:206–214
Anttila S, Hukkanen J, Hakkola J, Stjernvall T, Beaune P, Edwards RJ, Boobis AR, Pelkonen O, Raunio H (1997) Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mol Biol 16:242–249
Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391
Thervet E, Anglicheau D, King B, Schlageter MH, Cassinat B, Beaune P, Legendre C, Daly AK (2003) Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 76:1233–1235
Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ (2003) Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 3:477–483
Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199
Wang D, Johnson AD, Papp AC, Kroetz DL, Sadée W (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 15:693–704
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528
Johne A, Kopke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmoller J, Cascorbi I, Roots I (2002) Modulation of steady state kinetics of digoxin by haplotypes of the Pglycoprotein MDR1 gene. Clin Pharmacol Ther 72:574–594
Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, Beaune P, Legendre C, Thervet E (2003) Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 14:1889–1896
Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, Freund D, Schakel U, Ehninger G, Schaich M (2002) MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 62:4955–4962
Wasilewska A, Zalewski G, Chyczewski L, Zoch-Zwierz W (2007) MDR-1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children. Pediatr Nephrol 22:44–51
Jafar T, Prasad N, Agarwal V, Mahdi A, Gupta A, Sharma RK, Negi MP, Agrawal S (2011) MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant 26:3968–3974
Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS, Lee CG (2002) Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics 12:437–450
Pichard L, Fabre I, Daujat M, Domergue J, Joyeux H, Maurel P (1992) Effect of corticosteroids on the expression of cytochromes P450 and on cyclosporin A oxidase activity in primary cultures of human hepatocytes. Mol Pharmacol 41:1047–1055
Tada H, Tsuchida N, Satoh S, Kagaya H, Li Z, Sato K, Miura M, Suzuki T, Kato T, Habuchi T (2005) Impact of CYP3A5 and MDR1 (ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplant Proc 37:1730–1732
Ferraris JR, Argibay PF, Costa L, Jimenez G, Coccia PA, Ghezzi LF, Ferraris V, Belloso WH, Redal MA, Larriba JM (2011) Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids. Pediatr Transplant 15:525–532
Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Inoue T, Habuchi T, Suzuki T (2008) Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients. Steroids 73:1052–1059
Synold TW, Dussault I, Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7:584–590
Acknowledgments
This work was supported by grant VGHKS98-085 from Kaohsiung Veterans General Hospital, Taiwan, Republic of China.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Chiou, YH., Wang, LY., Wang, TH. et al. Genetic polymorphisms influence the steroid treatment of children with idiopathic nephrotic syndrome. Pediatr Nephrol 27, 1511–1517 (2012). https://doi.org/10.1007/s00467-012-2182-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-012-2182-0