Relationship Of Pharmacogenomics With Clinical Response Of Pulsed Cyclophosphamide Therapy In Lupus Nephritis

Purpose SLE is a chronic autoimmune disease characterized by multi-system damage.Prevalence in China is0.7-1/1000people, higher than in Western countries1/2000. The most common complication is kidney damage. Clinical trials have shown that cyclophosphamide is effective. There are individual differences in the efficacy of CPA. Single nucleotide polymorphisms (SNPs) of CYP2B6, CYP2C9, CYP2C19, GST and ABC gene result in the difference of enzyme activity,as encoding CPA metabolizing,detoxification and transport enzyme. Finally the outcome is the difference of clinical response and side effect. Our subject is to focus on the relationship between CYP2B6*4, CYP2B6*5, CYP2C9*3, CYP2C19*2, CYP2C19*3, GSTP1and ABCC4(rs9561778) with clinical efficacy and side-effect in lupus nephritis by retrospective analysis.This will helpful for individualized treatment in the future.Methods We studied60patients with biopsy-proven lupus nephritis (World Health Organization class Ⅲ、Ⅳ、Ⅴ、Ⅴ+Ⅲ、Ⅴ+Ⅳ) referred to the National Institutes of Health(NIH),who had been treated with prednisone and cyclophosphamide.The regimen is intravenous cyclophosphamide,targeting500-1000mg/m2of body surface area,given monthly for the first6months; oral prednisolone,1mg/kg/d, administered for6months. Evaluation of clinical efficacy for the24-hour urinary protein, creatinine and albumin levels are divided into complete remission CR, partial remission PR and none remission NR.We examined gene polymorphism of CYP2B6*4, CYP2B6*5, CYP2C9*3, CYP2C19*2, CYP2C19*3, GSTP1and ABCC4(rs9561778) by high-resolution melting analysis, which is more convenient, quick, accurate and inexpensive.This skill is easy to use in clinical. Then we analyzed the relationship between polymorphism and clinical response and side-sffect.Result1. The observed frequencies of the variant alleles CYP2B6*4, CYP2B6*5, CYP2C9*3, CYP2C19*2, CYP2C19*3, GSTP1and ABCC4(rs9561778) were50%、47.5%、3.3%、41.7%、6.7%、0、47.5%、respectively. CYP2B6*4, CYP2B6*5and GSTP1didn’t match Hardy-Weinberg balance (P=0.000, P=0.000,respectively). P values in Hardy-Weinberg genetic test of CYP2C19*2, ABCC4(rs9561778), CYP2C9*3, CYP2C19*3were1.000,0.604,0.980,0.314respectively,which was in line with the population genetic law.2. Complete remission CR and partial response PR normalized effective group.Single-gene analysis showed that CYP2B6*4, CYP2B6*5, CYP2C9*3, CYP2C19*2, CYP2C19*3and ABCC4(rs9561778) didn’t related to clinical outcome. Haplotype analysis of CYP2C19*2and ABCC4(rs9561778) revealed that allele A of CYP2C19*2and allele G of ABCC4(rs9561778)(A G) in two groups were significant different (P=0.009).CYP2C19*2A/A joint ABCC4(rs9561778) G/G or ABCC4(rs9561778) G/T in the effective group accounted for8.2%, which in the ineffective group is36.4%, there are different between two groups (P=0.031).3. Genotypes of CYP2B6*4, CYP2B6*5, CYP2C9*3, CYP2C19*2, CYP2C19*3, ABCC4(rs9561778)are’t related to the side-effect of pulse cyclophosphamide therpy in patients with lupus nephritis.Conclusions CYP2C19*2joint ABCC4(rs9561778) in patients with lupus nephritis may be related to treatment with CPA. The possibility of remission with CYP2C19*2A/A joint ABCC4(rs9561778) G/G or ABCC4(rs9561778) G/T is smaller than other genotypes and the polymorphism of CYP2B6*4, CYP2B6*5, CYP2C9*3, CYP2C19*3don’t influence the clinical effect about CPA.At the same time, this study did not find that polymorphism of CYP2B6*4, CYP2B6*5, CYP2C9*3, CYP2C19*2, CYP2C19*3and ABCC4(rs9561778)are related to the efficacy and side-effect of cyclophosphamide.