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.

Keywords::

• diabetic nephropathy
• oxidative stress
• genetic susceptibility
• GPX4
• NOX2

Acknowledgments

We thank Maria Auxiliadora Higa and Ana Mercedes Cavaleiro for the technical support.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

The Brazilian part of the study was supported by grants from “São Paulo Research Foundation“ (FAPESP; grants # 2009/09276-3, 2009/04162-0, and 2011/15015-8), “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq) and “Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre” (FIPE-HCPA), Brazil. The French part of the work was supported by grants from “Association Française des Diabétiques” (AFD), “Association Diabète Risque Vasculaire” (ADRV), and “Association L”Aide Aux Jeunes Diabétiques” (AJD), France.