title: Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide.
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.
  
  
  CONCLUSIONS
  This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.
authors.affiliation: Department of Internal Medicine, CHU Caen, Caen, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Audemard-Verger
authors.affiliation: Department of Internal Medicine, CHU Caen, Caen, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Martin Silva
authors.affiliation: Department of Pharmacology, Hôpital Kremlin Bicêtre, Kremlin Bicêtre, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.affiliation: Department of Internal Medicine, Hôpital Cochin, APHP, Université Paris V, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Costedoat-Chalumeau
authors.affiliation: Department of Nephrology, Hôpital Necker, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hummel
authors.affiliation: Department of Internal Medicine, Hôpital Cochin, APHP, Université Paris V, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Le Guern
authors.affiliation: Department of Internal Medicine, Hôpital Bichat, Paris, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Sacré
authors.affiliation: Department of Rheumatology, Hôpital Bichat, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Meyer
authors.affiliation: Department of Nephrology, Hôpital Bichat, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Daugas
authors.affiliation: Department of Internal Medicine, Hôpital Kremlin Bicêtre, Kremlin Bicêtre, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Goujard
authors.affiliation: Department of Internal Medicine, CHU Caen, Caen, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sultan
authors.affiliation: Department of Nephrology, CHU de Caen, Caen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lobbedez
authors.affiliation: Department of Clinical Immuno-pathology, Hôpital Saint Louis, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.affiliation: Department of Nephrology and Clinical Immunology, CHU Toulouse, Toulouse, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pourrat
authors.affiliation: Department of Vascular Medicine, CHU Caen, Caen, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Le Hello
authors.affiliation: Department of Nephrology, CHU Rouen, Rouen, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Godin
authors.affiliation: Biostatistics Unity, CHU Caen, Caen, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Morello
authors.affiliation: Department of Internal Medicine, CHU Lille, Lille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lambert
authors.affiliation: Department of Internal Medicine, CHU Lille, Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.affiliation: Department of Nephrology, CH Valenciennes, Valenciennes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vanhille
authors.affiliation: Department of Nephrology, CH Cherbourg, Cherbourg, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Queffeulou
authors.affiliation: Department of Nephrology, CH Cherbourg, Cherbourg, France.
authors.forename: Jacky
authors.initials: J
authors.lastname: Potier
authors.affiliation: Department of Nephrology, CH Charleville Mézière, Charleville Mézière, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Dion
authors.affiliation: Department of Nephrology, CH Boulogne-sur-Mer, Boulogne-sur-Mer, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bataille
authors.affiliation: Department of Nephrology and Clinical Immunology, CHU Toulouse, Toulouse, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Chauveau
authors.affiliation: Department of Internal Medicine, CHU Toulouse, France; UMR 1027 Inserm-Univeristy of Toulouse, France; CIC 1436, Toulouse, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Moulis
authors.affiliation: Department of Internal Medicine, Hôpital Saint Louis, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Farge-Bancel
authors.affiliation: Department of Internal Medicine, CHU Amiens, Amiens, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Duhaut
authors.affiliation: Department of Rheumatology, Hôpital Aulnay-sous-bois, Aulnay-sous-bois, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Saint-Marcoux
authors.affiliation: Department of Internal Medicine, CHU Grenoble, Grenoble, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Deroux
authors.affiliation: Department of Immunology, Institut Cochin, Paris, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Manuzak
authors.affiliation: Department of Dermatology, Hôpital Tenon, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Francès
authors.affiliation: Department of Internal Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Aumaitre
authors.affiliation: Department of Internal Medicine, CHU Limoges, Limoges, France.
authors.forename: Holy
authors.initials: H
authors.lastname: Bezanahary
authors.affiliation: Department of Pharmacology, Hôpital Kremlin Bicêtre, Kremlin Bicêtre, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
authors.affiliation: Department of Internal Medicine, CHU Caen, Caen, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Bienvenu
mesh_terms: D000328:Adult; D003404:Creatinine / Q000097:blood; D003520:Cyclophosphamide / Q000627:therapeutic use*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008181:Lupus Nephritis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011507:Proteinuria / Q000652:urine; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D003404:Creatinine; D003520:Cyclophosphamide; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007166:Immunosuppressive Agents; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human