Epistatic Interactions Among CYP2C19*2, CYP3A4 and GSTP1 on the Cyclophosphamide Therapy in Lupus Nephritis Patients

Abstract

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

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

“…Future studies to confirm the role of the CYP2B6 and CYP2C19 pharmacogenes should include investigation of epistatic gene–gene interactions using appropriate statistical analysis such as multifactor dimensionality reduction or reporting individual patients combined genotype at the 2 gene loci. This multivariate approach has already shown some utility in population sizes between 189 and 567 patients . Remarkably, considering the important role in the inactivation of 4‐OHCP, few studies have included the assessment of ALDH1A1 on clinical response to cyclophosphamide therapy.…”

“…A preliminary assessment in a small group of lupus nephritis patients ( n = 16) suggested that the combination genotype based on these 2 pharmacogenes may relate to the bioactivation ratio . A further study assessed cyclophosphamide and 4‐OHCP pharmacokinetics in 18 lupus nephritis patients did not find an association with CYP2C19 genotype but did not determine CYP2B6 genotype. However, a large study (189 SLE patients) found strong correlations between both CYP2C19 and CYP2B6 variants and 4‐OHCP plasma concentrations .…”

“…Most recently, a combined genetic marker ( CYP2C19*2 and CYP2B6 ‐750C) significantly associated with worse disease remission and longer response time in a gene‐dose dependent manner in SLE patients ( n = 189) . A further study ( n = 136) of lupus nephritis patients also found that CYP2C19*2 genotype associated with poor response . Additional epistatic effects of CYP3A4 and GSTP1 were suggested.…”

“…It is clear that the majority of the therapeutic outcome or pharmacokinetic studies have focussed on CYP2B6 and/or CYP2C19 as candidate genes. However, some studies have also reported on selected SNP in other candidate genes such as CYP2C9 , GST or ABCB1 . Whilst not the focus of this review, it is important to note that the role of pharmacogenetics in the risk of excessive toxicity (due to high levels of bioactivation of this cytotoxic drug) have also been assessed.…”

“…51 A further study (n = 136) of lupus nephritis patients also found that CYP2C19*2 genotype associated with poor response. 50 Additional epistatic effects Alleles are as described in Table 1 Alleles are as described in Table 1 In a study of patients with renal disease due to vasculitis (n = 93), no association between response and CYP2C19*2 or CYP2B6 (1459C>T) genotype was observed. 68 Other important CYP2B6 variants and haplotypes were not assessed.…”