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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 O 2  •-  (-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 m 2  (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.

bmc medical genetics

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