Epistatic interactions among CYP2C19*2, CYP3A4 and GSTP1 on the cyclophosphamide therapy in lupus nephritis patients

Pharmacogenomics. 2017 Oct;18(15):1401-1411. doi: 10.2217/pgs-2017-0069. Epub 2017 Oct 4.

Abstract

Aim: To investigate the impact of genetic variants in CYP2C9, CYP2C19, CYP3A4, GSTT1, GSTM1 and GSTP1 on the efficacy of cyclophosphamide (CYC) therapy in patients with lupus nephritis.

Materials & methods: Lupus nephritis patients (n = 220) treated with CYC were included in the study.

Results: Logistic regression analysis identified CYP2C19*2 as an independent predictor of CYC therapeutic failure (odds ratio [OR]: 2.69; p = 0.0043). Bivariate and trivariate analysis showed the subjects harboring CYP2C19*2 and GSTP1 (OR: 3.25; p = 0.03), and CYP2C19*2, GSTP1 and CYP3A5*3 have synergistic influence on CYC failure (OR: 8.2; p < 0.0001). Significant decrease in AUC0-t, Cmax and t½ of 4-OH-CYC in patients carrying CYP3A5*3 (p < 0.02).

Conclusion: Patients with CYP2C19*2 were at increased risk and CYP2C19*2, CYP3A5*3 and GSTP1 have synergistic influence on CYC failure.

Keywords: 4-OH-cyclophosphamide; cyclophoshamide; lupus nephritis; pharmacogenetics; systemic lupus erythematosus.

MeSH terms

  • Adult
  • Cyclophosphamide / therapeutic use*
  • Cytochrome P-450 CYP2C19 / genetics*
  • Cytochrome P-450 CYP3A / genetics*
  • Female
  • Glutathione S-Transferase pi / genetics*
  • Humans
  • Lupus Nephritis / drug therapy*
  • Lupus Nephritis / genetics*
  • Male
  • Polymorphism, Single Nucleotide / genetics*
  • Treatment Failure

Substances

  • Cyclophosphamide
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • GSTP1 protein, human
  • Glutathione S-Transferase pi