Influence of glutathione S transferase A1 gene polymorphism (-69C > T, rs3957356) on intravenous cyclophosphamide efficacy and side effects: a case-control study in Egyptian patients with lupus nephritis.

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. Cyclophosphamide (CYC) is a cytotoxic drug of a narrow therapeutic window that is commonly used in lupus nephritis (LN) treatment. However, 30-40% of patients experience CYC resistance. CYC inactivation is mediated by the glutathione S transferases (GSTs) superfamily: GST class A (GSTA) has the greatest activity and contains 5 isoenzymes. Polymorphisms of genes involved in the drug metabolism could alter the drug pharmacokinetics and effectiveness. CYC pharmacokinetics and pharmacogenomics are extensively studied in malignancies; however, scarce data are available about this issue in the autoimmune rheumatic diseases. Prediction of the drug response helps the achievement of the highest benefit-to-risk ratio. The aim of this case-control study was to address the association between GSTA1 polymorphism (-69C > T, rs3957356), and the rate of response to and side effects of intravenous CYC in LN patients. Ninety-four patients were included and divided into matched groups: resistant and responsive. Genotyping was performed using restriction fragment length polymorphism method after amplification. A significant association between the TT genotype, and CYC resistance and partial response was observed. Concerning the recessive model, none of the patients within the TT group achieved complete remission. CYC side effects were more common with the polymorphism under the genotype, recessive model, and allele distributions. When patients' pre- and post-treatment characteristics were compared, patients with the TT genotype did not show any significant improvement. LN patients with GSTA1 (-69C > T, rs3957356) TT genotype have the highest risk of CYC unresponsiveness and toxicity. Key-Points • LN patients with the wild genotype of GSTA1 have the greatest probability of achieving a complete renal response to IV CYC. • The homozygous GSTA1 (-69C > T, rs3957356) TT genotype is associated with the highest risk of LN unresponsiveness to IV CYC. • The homozygous GSTA1 (-69C > T, rs3957356) TT genotype is associated with the highest risk of CYC-related side effects.