title: Glutathione peroxidase-1 gene (GPX1) variants, oxidative stress and risk of kidney complications in people with type 1 diabetes.
abstract: OBJECTIVE
  Glutathione peroxidase (GPX) is a class of antioxidant enzymes that catalyze the reduction of hydrogen peroxide to water. GPX1 is the most abundant isoform and is expressed in all kidney cells. Isoprostane and advanced oxidation protein products (AOPP) were identified as markers of oxidative stress in patients with kidney disease. We investigated associations of GPX1 genotypes with kidney complications, and with plasma concentrations of isoprostane and AOPP in type 1 diabetic patients.
  
  
  METHODS
  Four SNPs in the GPX1 gene region were genotyped in SURGENE (n=340; 10-year follow-up); GENEDIAB (n=461) and GENESIS (n=584) cohorts of type 1 diabetic patients. Subsets of GENEDIAB (n=237) and GENESIS (n=466) participants were followed up for 9 and 5years, respectively. Plasma concentrations of isoprostane and AOPP were measured at baseline in GENEDIAB. Hazard ratios (HR) were estimated for incidence of kidney complications.
  
  
  RESULTS
  In SURGENE, 98 renal events (new cases of microalbuminuria or progression to more severe stage of diabetic nephropathy) occurred during follow-up. The minor T-allele of rs3448 was associated with the incidence of renal events (HR 1.81, 95% CI 1.16-2.84, p=0.008). In GENESIS/GENEDIAB pooled study, end stage renal disease (ESRD) occurred during follow-up in 52 individuals. The same variant was associated with the incidence of ESRD (HR 3.34, 95% CI, 1.69-6.98, p=0.0004). The variant was also associated with higher plasma isoprostane concentration in GENEDIAB cohort: 2.02±0.12 (TT+CT) vs 1.75±0.13 (CC) ng/mL (p=0.009), and with higher plasma AOPP in the subset of participants with the baseline history of ESRD (TT+CT 67±6 vs CC 48±6μmol/L, p=0.006).
  
  
  CONCLUSIONS
  The minor T-allele of rs3448 was associated with kidney complications (incidences of microalbuminuria, renal events and ESRD) in patients with type 1 diabetes. The risk allele was associated with higher plasma concentrations of isoprostane and AOPP. Our results are consistent with the implication of GPX1 in the mechanism of renal protection against oxidative stress in type 1 diabetic patients.
authors.affiliation: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006, Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75018, Paris, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mohammedi
authors.affiliation: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006, Paris, France; Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Avenida Dr. Arnaldo 455, CEP 01246903, São Paulo, SP, Brazil.
authors.forename: Thiago A
authors.initials: TA
authors.lastname: Patente
authors.affiliation: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006, Paris, France.
authors.forename: Naima
authors.initials: N
authors.lastname: Bellili-Muñoz
authors.affiliation: INSERM, Research Unit 773, 16 rue Henri Huchard, 75018, Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Biochemistry, 46 rue Henri Huchard, 75018, Paris, France.
authors.forename: Fathi
authors.initials: F
authors.lastname: Driss
authors.affiliation: INSERM, Research Unit 1137 - IAME, 16 rue Henri Huchard, 75018, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Nagard
authors.affiliation: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, 16 rue Henri Huchard, 75018, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fumeron
authors.affiliation: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006, Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75018, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, 16 rue Henri Huchard, 75018, Paris, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.affiliation: Centre Hospitalier Universitaire de Poitiers, Department of Endocrinology and Diabetology, 2 rue de la Milétrie, 86021, Poitiers, France; INSERM, Research Unit 1082, 2 rue de la Milétrie, 86021, Poitiers, France; INSERM, CIC 1402, 2 rue de la Milétrie, 86021, Poitiers, France; Université de Poitiers, UFR de Médecine et Pharmacie, 6 rue de la Milétrie, 86073, Poitiers, France.
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Avenida Dr. Arnaldo 455, CEP 01246903, São Paulo, SP, Brazil; Centro de Terapia Celular e Molecular (NUCEL/NETCEM) da FMUSP, Avenida Dr. Arnaldo 455, CEP 01246903, São Paulo, SP, Brazil.
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Corrêa-Giannella
authors.affiliation: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006, Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75018, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, 16 rue Henri Huchard, 75018, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.affiliation: INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine, 75006, Paris, France. Electronic address: gilberto.velho@inserm.fr.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Velho
mesh_terms: D000328:Adult; D062107:Advanced Oxidation Protein Products / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology*; D005260:Female; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D028421:Isoprostanes / Q000097:blood; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D000094765:Glutathione Peroxidase GPX1
chemical_list: D062107:Advanced Oxidation Protein Products; D028421:Isoprostanes; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human
keywords: Diabetic nephropathy; Genetic association; Glutathione peroxidase; Oxidative stress; Type 1 diabetes