Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide

Alexandra Audemard-Verger, Nicolas Martin Silva, Céline Verstuyft, Nathalie Costedoat-Chalumeau, Aurélie Hummel, Véronique Le Guern, Karim Sacré, Olivier Meyer, Eric Daugas, Cécile Goujard, Audrey Sultan, Thierry Lobbedez, Lionel Galicier, Jacques Pourrat, Claire Le Hello, Michel Godin, Rémy Morello, Marc Lambert, Eric Hachulla, Philippe VanhilleGuillaume Queffeulou, Jacky Potier, Jean Jacques Dion, Pierre Bataille, Dominique Chauveau, Guillaume Moulis, Dominique Farge-Bancel, Pierre Duhaut, Bernadette Saint-Marcoux, Alban Deroux, Jennifer Manuzak, Camille Francès, Olivier Aumaitre, Holy Bezanahary, Laurent Becquemont, Boris Bienvenu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Objective To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). Methods We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria 0.33g/day and serum creatinine 124 μmol/l. Partial remission (PR) was defined as proteinuria -1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline. Results Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile!105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile!105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02-24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. Conclusion This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.

Original languageEnglish (US)
Article numbere0151696
JournalPLoS One
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

Fingerprint

nephritis
Lupus Nephritis
cyclophosphamide
Glutathione Transferase
Polymorphism
glutathione transferase
Cyclophosphamide
remission
Drug-Related Side Effects and Adverse Reactions
genetic polymorphism
drugs
Genotype
Proteinuria
Cytochromes
Pharmaceutical Preparations
genotype
kidneys
Creatinine
cytochromes
Kidney

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Audemard-Verger, A., Silva, N. M., Verstuyft, C., Costedoat-Chalumeau, N., Hummel, A., Le Guern, V., ... Bienvenu, B. (2016). Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide. PLoS One, 11(3), [e0151696]. https://doi.org/10.1371/journal.pone.0151696

Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide. / Audemard-Verger, Alexandra; Silva, Nicolas Martin; Verstuyft, Céline; Costedoat-Chalumeau, Nathalie; Hummel, Aurélie; Le Guern, Véronique; Sacré, Karim; Meyer, Olivier; Daugas, Eric; Goujard, Cécile; Sultan, Audrey; Lobbedez, Thierry; Galicier, Lionel; Pourrat, Jacques; Le Hello, Claire; Godin, Michel; Morello, Rémy; Lambert, Marc; Hachulla, Eric; Vanhille, Philippe; Queffeulou, Guillaume; Potier, Jacky; Dion, Jean Jacques; Bataille, Pierre; Chauveau, Dominique; Moulis, Guillaume; Farge-Bancel, Dominique; Duhaut, Pierre; Saint-Marcoux, Bernadette; Deroux, Alban; Manuzak, Jennifer; Francès, Camille; Aumaitre, Olivier; Bezanahary, Holy; Becquemont, Laurent; Bienvenu, Boris.

In: PLoS One, Vol. 11, No. 3, e0151696, 01.03.2016.

Research output: Contribution to journalArticle

Audemard-Verger, A, Silva, NM, Verstuyft, C, Costedoat-Chalumeau, N, Hummel, A, Le Guern, V, Sacré, K, Meyer, O, Daugas, E, Goujard, C, Sultan, A, Lobbedez, T, Galicier, L, Pourrat, J, Le Hello, C, Godin, M, Morello, R, Lambert, M, Hachulla, E, Vanhille, P, Queffeulou, G, Potier, J, Dion, JJ, Bataille, P, Chauveau, D, Moulis, G, Farge-Bancel, D, Duhaut, P, Saint-Marcoux, B, Deroux, A, Manuzak, J, Francès, C, Aumaitre, O, Bezanahary, H, Becquemont, L & Bienvenu, B 2016, 'Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide', PLoS One, vol. 11, no. 3, e0151696. https://doi.org/10.1371/journal.pone.0151696
Audemard-Verger A, Silva NM, Verstuyft C, Costedoat-Chalumeau N, Hummel A, Le Guern V et al. Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide. PLoS One. 2016 Mar 1;11(3). e0151696. https://doi.org/10.1371/journal.pone.0151696
Audemard-Verger, Alexandra ; Silva, Nicolas Martin ; Verstuyft, Céline ; Costedoat-Chalumeau, Nathalie ; Hummel, Aurélie ; Le Guern, Véronique ; Sacré, Karim ; Meyer, Olivier ; Daugas, Eric ; Goujard, Cécile ; Sultan, Audrey ; Lobbedez, Thierry ; Galicier, Lionel ; Pourrat, Jacques ; Le Hello, Claire ; Godin, Michel ; Morello, Rémy ; Lambert, Marc ; Hachulla, Eric ; Vanhille, Philippe ; Queffeulou, Guillaume ; Potier, Jacky ; Dion, Jean Jacques ; Bataille, Pierre ; Chauveau, Dominique ; Moulis, Guillaume ; Farge-Bancel, Dominique ; Duhaut, Pierre ; Saint-Marcoux, Bernadette ; Deroux, Alban ; Manuzak, Jennifer ; Francès, Camille ; Aumaitre, Olivier ; Bezanahary, Holy ; Becquemont, Laurent ; Bienvenu, Boris. / Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide. In: PLoS One. 2016 ; Vol. 11, No. 3.
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abstract = "Objective To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). Methods We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria 0.33g/day and serum creatinine 124 μmol/l. Partial remission (PR) was defined as proteinuria -1.5g/day with a 50{\%} decrease of the baseline proteinuria value and serum creatinine no greater than 25{\%} above baseline. Results Most patients were women (84{\%}) and 77{\%} were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile!105Val GSTP1 genotype were respectively 38{\%}, 60{\%} and 44{\%}. In multivariate analysis, the Ile!105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95{\%} CI [1.02-24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95{\%} CI [1.064-10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. Conclusion This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.",
author = "Alexandra Audemard-Verger and Silva, {Nicolas Martin} and C{\'e}line Verstuyft and Nathalie Costedoat-Chalumeau and Aur{\'e}lie Hummel and {Le Guern}, V{\'e}ronique and Karim Sacr{\'e} and Olivier Meyer and Eric Daugas and C{\'e}cile Goujard and Audrey Sultan and Thierry Lobbedez and Lionel Galicier and Jacques Pourrat and {Le Hello}, Claire and Michel Godin and R{\'e}my Morello and Marc Lambert and Eric Hachulla and Philippe Vanhille and Guillaume Queffeulou and Jacky Potier and Dion, {Jean Jacques} and Pierre Bataille and Dominique Chauveau and Guillaume Moulis and Dominique Farge-Bancel and Pierre Duhaut and Bernadette Saint-Marcoux and Alban Deroux and Jennifer Manuzak and Camille Franc{\`e}s and Olivier Aumaitre and Holy Bezanahary and Laurent Becquemont and Boris Bienvenu",
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T1 - Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide

AU - Audemard-Verger, Alexandra

AU - Silva, Nicolas Martin

AU - Verstuyft, Céline

AU - Costedoat-Chalumeau, Nathalie

AU - Hummel, Aurélie

AU - Le Guern, Véronique

AU - Sacré, Karim

AU - Meyer, Olivier

AU - Daugas, Eric

AU - Goujard, Cécile

AU - Sultan, Audrey

AU - Lobbedez, Thierry

AU - Galicier, Lionel

AU - Pourrat, Jacques

AU - Le Hello, Claire

AU - Godin, Michel

AU - Morello, Rémy

AU - Lambert, Marc

AU - Hachulla, Eric

AU - Vanhille, Philippe

AU - Queffeulou, Guillaume

AU - Potier, Jacky

AU - Dion, Jean Jacques

AU - Bataille, Pierre

AU - Chauveau, Dominique

AU - Moulis, Guillaume

AU - Farge-Bancel, Dominique

AU - Duhaut, Pierre

AU - Saint-Marcoux, Bernadette

AU - Deroux, Alban

AU - Manuzak, Jennifer

AU - Francès, Camille

AU - Aumaitre, Olivier

AU - Bezanahary, Holy

AU - Becquemont, Laurent

AU - Bienvenu, Boris

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Objective To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). Methods We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria 0.33g/day and serum creatinine 124 μmol/l. Partial remission (PR) was defined as proteinuria -1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline. Results Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile!105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile!105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02-24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. Conclusion This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.

AB - Objective To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). Methods We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria 0.33g/day and serum creatinine 124 μmol/l. Partial remission (PR) was defined as proteinuria -1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline. Results Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile!105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile!105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02-24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. Conclusion This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.

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