title: Sex-specific associations of variants in regulatory regions of NADPH oxidase-2 (CYBB) and glutathione peroxidase 4 (GPX4) genes with kidney disease in type 1 diabetes.
abstract: Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide-generating nicotinamide adenine dinucleotide phosphate-oxidase 2 (NOX2, encoded by the CYBB gene) and the antioxidant enzyme glutathione peroxidase 4 (GPX4) play opposing roles in the balance of cellular redox status. In the present study, we investigated associations of single nucleotide polymorphisms (SNPs) in the regulatory regions of CYBB and GPX4 with kidney disease in patients with type 1 diabetes. Two functional SNPs, rs6610650 (CYBB promoter region, chromosome X) and rs713041 (GPX4 3'untranslated region, chromosome 19), were genotyped in 451 patients with type 1 diabetes from a Brazilian cohort (diabetic nephropathy: 44.6%) and in 945 French/Belgian patients with type 1 diabetes from Genesis and GENEDIAB cohorts (diabetic nephropathy: 62.3%). The minor A-allele of CYBB rs6610650 was associated with lower estimated glomerular filtration rate (eGFR) in Brazilian women, and with the prevalence of established/advanced nephropathy in French/Belgian women (odds ratio 1.75, 95% CI 1.11-2.78, p = 0.016). The minor T-allele of GPX4 rs713041 was inversely associated with the prevalence of established/advanced nephropathy in Brazilian men (odds ratio 0.30, 95% CI 0.13-0.68, p = 0.004), and associated with higher eGFR in French/Belgian men. In conclusion, these heterogeneous results suggest that neither CYBB nor GPX4 are major genetic determinants of diabetic nephropathy, but nevertheless, they could modulate in a gender-specific manner the risk for renal disease in patients with type 1 diabetes.
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo , São Paulo-SP , Brazil.
authors.forename: M B
authors.initials: MB
authors.lastname: Monteiro
authors.forename: T A
authors.initials: TA
authors.lastname: Patente
authors.forename: K
authors.initials: K
authors.lastname: Mohammedi
authors.forename: M S
authors.initials: MS
authors.lastname: Queiroz
authors.forename: M J
authors.initials: MJ
authors.lastname: Azevedo
authors.forename: L H
authors.initials: LH
authors.lastname: Canani
authors.forename: M C
authors.initials: MC
authors.lastname: Parisi
authors.forename: M
authors.initials: M
authors.lastname: Marre
authors.forename: G
authors.initials: G
authors.lastname: Velho
authors.forename: M L
authors.initials: ML
authors.lastname: Corrêa-Giannella
mesh_terms: D000328:Adult; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D008562:Membrane Glycoproteins; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases