title: Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus.
abstract: BACKGROUND
  Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the CYBA gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O₂•⁻ (-675 T → A in CYBA, unregistered) and in glutathione metabolism (-129 C → T in GCLC [rs17883901] and -65 T → C in GPX3 [rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients.
  
  
  METHODS
  401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: ≥ 60 mL (n = 265) or < 60 mL/min/1.73 m² (n = 136) and were genotyped.
  
  
  RESULTS
  No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying CYBA genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying GCLC genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (p = 0.0082). Logistic regression analysis identified the presence of at least one A allele of the CYBA SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, p = 0.0354) and the presence of at least one T allele of the GCLC rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, p = 0.0068).
  
  
  CONCLUSIONS
  The functional SNPs CYBA -675 T → A and GCLC rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo, 01246-903 São Paulo-SP, Brazil.
authors.forename: Suzana M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Maria B
authors.initials: MB
authors.lastname: Monteiro
authors.forename: Tatiana
authors.initials: T
authors.lastname: Marques
authors.forename: Ana M
authors.initials: AM
authors.lastname: Luna
authors.forename: Maria A
authors.initials: MA
authors.lastname: Fortes
authors.forename: Márcia
authors.initials: M
authors.lastname: Nery
authors.forename: Márcia
authors.initials: M
authors.lastname: Queiroz
authors.forename: Sérgio A
authors.initials: SA
authors.lastname: Dib
authors.forename: Márcio F
authors.initials: MF
authors.lastname: Vendramini
authors.forename: Mirela J
authors.initials: MJ
authors.lastname: Azevedo
authors.forename: Luis H
authors.initials: LH
authors.lastname: Canani
authors.forename: Maria C
authors.initials: MC
authors.lastname: Parisi
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Pavin
authors.forename: Daniel
authors.initials: D
authors.lastname: Giannella-Neto
authors.forename: Maria L
authors.initials: ML
authors.lastname: Corrêa-Giannella
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D020134:Catalytic Domain / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: C486484:GPX3 protein, human; D005979:Glutathione Peroxidase; D019255:NADPH Oxidases; C086986:CYBA protein, human; D005721:Glutamate-Cysteine Ligase