title: RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20-year follow-up.
abstract: OBJECTIVE
  We investigated the association of polymorphisms of three genes implicated in oxidative stress: CYBA C242T, RAGE -374T/A and -429T/C, and ALOX12 Arg261Gln, with the delay of microalbuminuria onset in patients with type 1 diabetes mellitus (DT1).
  
  
  METHODS
  A total of 162 T1D patients presenting with diabetes for 32.9 ± 9 years were included in the study; 53 had persistent microalbuminuria (>30 mg/l) and 109 did not. Onset of diabetes, microalbuminuria and end-stage renal disease (ESRD) were recorded as bio-clinical data. We determined polymorphism association of microalbuminuria with a Cox regression model.
  
  
  RESULTS
  All polymorphisms respected the Hardy-Weinberg equilibrium. The Cox regression model validated four significant variables associated with microalbuminuria: RAGE 374AA (HR 4.19 [1.84-9.58] (p = 0.001)), CYBA TT+TC (HR 2.1 [1.16-3.80], p = 0.015), male sex (HR 1.92 [1.07-3.43], p = 0.028) and diabetes diagnosis at the pediatric stage (HR 1.85 [1.03-3.32], p = 0.039). The same association was found with ESRD (p = 0.028 and p = 0.033 for CYBA TC+TT and RAGE 374AA, respectively). CYBA C242T and RAGE 374T/A were not significantly associated with diabetic retinopathy.
  
  
  CONCLUSIONS
  CYBA C242T and RAGE -374T/A correlate with microalbuminuria onset in the French DT1 cohort. The same correlation with ESRD onset supports the argument for the involvement of a genetic predisposition involving kidney-specific oxidative stress for diabetic nephropathy.
authors.affiliation: Department of Nephrology, Nephrology Clinic, Grenoble University Hospital, Grenoble, 38043, France. benoit.franko@orange.fr.|Chronic Granulomatous Disease Diagnosis and Research Centre, Therex-TIMC/Imag, UMR CNRS 5525, UJF-Grenoble 1, Université Grenoble Alpes, Grenoble, 38041, France. benoit.franko@orange.fr.
authors.forename: Benoit
authors.identifier: http://orcid.org/0000-0001-9945-9919
authors.initials: B
authors.lastname: Franko
authors.affiliation: Department of Endocrinology, Grenoble University Hospital, Grenoble, 38043, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Benhamou
authors.affiliation: UJF-Grenoble 1/CNRS/Clinical Research Centre-Inserm CIC03/TIMC-IMAG UMR 5525/Themas, Grenoble University Hospital, Grenoble, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Genty
authors.affiliation: Department of Nephrology, Nephrology Clinic, Grenoble University Hospital, Grenoble, 38043, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jouve
authors.affiliation: Department of Endocrinology, Grenoble University Hospital, Grenoble, 38043, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Nasse
authors.affiliation: Chronic Granulomatous Disease Diagnosis and Research Centre, Therex-TIMC/Imag, UMR CNRS 5525, UJF-Grenoble 1, Université Grenoble Alpes, Grenoble, 38041, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Rzeoecki
authors.affiliation: Chronic Granulomatous Disease Diagnosis and Research Centre, Therex-TIMC/Imag, UMR CNRS 5525, UJF-Grenoble 1, Université Grenoble Alpes, Grenoble, 38041, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Semeraro
authors.affiliation: Chronic Granulomatous Disease Diagnosis and Research Centre, Therex-TIMC/Imag, UMR CNRS 5525, UJF-Grenoble 1, Université Grenoble Alpes, Grenoble, 38041, France.|CGD Centre, BEP/DBTP/Pôle Biologie, CHU de Grenoble, Grenoble, 38043, France.
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Stasia
authors.affiliation: Department of Nephrology, Nephrology Clinic, Grenoble University Hospital, Grenoble, 38043, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Zaoui
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics*; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D019255:NADPH Oxidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000951:Antigens, Neoplasm; D019255:NADPH Oxidases; C086986:CYBA protein, human; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
keywords: CYBA; Diabetic nephropathy; Genetic polymorphisms; RAGE; Type 1 diabetes