title: Manganese superoxide dismutase (SOD2) polymorphisms, plasma advanced oxidation protein products (AOPP) concentration and risk of kidney complications in subjects with type 1 diabetes.
abstract: OBJECTIVE
  Oxidative stress is involved in the pathophysiology of diabetic nephropathy. Manganese superoxide dismutase (SOD2) catalyses the dismutation of superoxide, regulates the metabolism of reactive oxygen species in the mitochondria and is highly expressed in the kidney. Plasma concentration of advanced oxidation protein products (AOPP), a marker of oxidative stress, was found to be increased in patients with kidney disease. We investigated associations of SOD2 allelic variations, plasma SOD activity and AOPP concentration with diabetic nephropathy in type 1 diabetic subjects.
  
  
  METHODS
  Eight SNPs in the SOD2 region were analysed in 1285 Caucasian subjects with type 1 diabetes from the SURGENE prospective study (n = 340; 10-year follow-up), GENESIS (n = 501) and GENEDIAB (n = 444) cross-sectional studies. Baseline plasma concentration of AOPP and SOD activity were measured in GENEDIAB participants. Hazard ratio (HR) and odds ratio (OR) were determined for incidence and prevalence of nephropathy. Analyses were adjusted or stratified by retinopathy stages.
  
  
  RESULTS
  In the SURGENE cohort, the T-allele of rs4880 (V16A) was associated with the incidence of renal events (new cases, or the progression to a more severe stage of nephropathy; HR 1.99, 95% CI 1.24-3.12, p = 0.004) and with the decline in estimated glomerular filtration rate (eGFR) during follow-up. Similar associations were observed for rs2758329 and rs8031. Associations were replicated in GENESIS/GENEDIAB cohorts, in the subset of participants without proliferative retinopathy, and were confirmed by haplotype analyses. Risk allele and haplotype were also associated with higher plasma AOPP concentration and lower SOD activity.
  
  
  CONCLUSIONS
  SOD2 allelic variations were associated with the incidence and the progression of diabetic nephropathy, with a faster decline in eGFR and with plasma AOPP concentration and SOD activity in subjects with type 1 diabetes. These results are consistent with a role for SOD2 in the protection against oxidative stress and kidney disease in type 1 diabetes.
authors.affiliation: Research Unit 1138, INSERM, Paris, France; Department of Diabetology, Endocrinology and Nutrition, Assistance Publique Hôpitaux de Paris - Bichat Hospital, Paris, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mohammedi
authors.affiliation: Research Unit 1138, INSERM, Paris, France.
authors.forename: Naïma
authors.initials: N
authors.lastname: Bellili-Muñoz
authors.affiliation: Research Unit 773, INSERM, Paris, France; Department of Biochemistry, Assistance Publique Hôpitaux de Paris - Bichat Hospital, Paris, France.
authors.forename: Fathi
authors.initials: F
authors.lastname: Driss
authors.affiliation: Research Unit 1138, INSERM, Paris, France; Department of Diabetology, Endocrinology and Nutrition, Assistance Publique Hôpitaux de Paris - Bichat Hospital, Paris, France; UFR de Médecine, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.affiliation: Department of Biochemistry, Assistance Publique Hôpitaux de Paris - Bichat Hospital, Paris, France; UFR de Pharmacie, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Seta
authors.affiliation: Research Unit 1138, INSERM, Paris, France; UFR de Médecine, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fumeron
authors.affiliation: Department of Endocrinology and Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France; Research Unit 1082, INSERM, Poitiers, France; Centre d'Investigation Clinique (CIC) 0802, INSERM, Poitiers, France; UFR de Médecine et Pharmacie, Université de Poitiers, Poitiers, France.
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.affiliation: Research Unit 1138, INSERM, Paris, France; Department of Diabetology, Endocrinology and Nutrition, Assistance Publique Hôpitaux de Paris - Bichat Hospital, Paris, France; UFR de Médecine, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.affiliation: Research Unit 1138, INSERM, Paris, France.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Velho
mesh_terms: D000328:Adult; D062107:Advanced Oxidation Protein Products / Q000097:blood*; D000483:Alleles; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000097:blood* / Q000209:etiology / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D011446:Prospective Studies; D013482:Superoxide Dismutase / Q000097:blood* / Q000235:genetics; D055815:Young Adult
chemical_list: D062107:Advanced Oxidation Protein Products; D013482:Superoxide Dismutase