title: Allelic variations in the CYBA gene of NADPH oxidase and risk of kidney complications in patients with type 1 diabetes.
abstract: Oxidative stress plays a pivotal role in the pathophysiology of diabetic nephropathy, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system is an important source of reactive oxygen species in hyperglycemic conditions in the kidney. Plasma concentration of advanced oxidation protein products (AOPP), a marker of oxidative stress, is increased in patients with diabetic nephropathy. We investigated associations of variants in the CYBA gene, encoding the regulatory subunit p22(phox) of NADPH oxidase, with diabetic nephropathy and plasma AOPP and myeloperoxidase (MPO) concentrations in type 1 diabetic patients. Seven SNPs in the CYBA region were analyzed in 1357 Caucasian subjects with type 1 diabetes from the SURGENE (n=340), GENEDIAB (n=444), and GENESIS (n=573) cohorts. Duration of follow-up was 10, 9, and 6 years, respectively. Cox proportional hazards and logistic regression analyses were used to estimate hazard ratios (HR) or odds ratios (OR) for incidence and prevalence of diabetic nephropathy. The major G-allele of rs9932581 was associated with the incidence of renal events defined as new cases of microalbuminuria or the progression to a more severe stage of nephropathy during follow-up (HR 1.59, 95% CI 1.17-2.18, P=0.003) in SURGENE. The same allele was associated with established/advanced nephropathy (OR 1.52, 95% CI 1.22-1.92, P=0.0001) and with the incidence of end-stage renal disease (ESRD) (HR 2.01, 95% CI 1.30-3.24, P=0.001) in GENEDIAB/GENESIS pooled studies. The risk allele was also associated with higher plasma AOPP concentration in subsets of SURGENE and GENEDIAB, with higher plasma MPO concentration in a subset of GENEDIAB, and with lower estimated glomerular filtration rate (eGFR) in the three cohorts. In conclusion, a functional variant in the promoter of the CYBA gene was associated with lower eGFR and with prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. These results are consistent with a role for NADPH oxidase in the pathophysiology of kidney complications of diabetes.
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France; Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Avenida Dr. Arnaldo 455, CEP 01246903, São Paulo, SP, Brazil.
authors: Thiago A
authors: TA
authors: Patente
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75018 Paris, France.
authors: Kamel
authors: K
authors: Mohammedi
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France.
authors: Naïma
authors: N
authors: Bellili-Muñoz
authors: INSERM, Research Unit 773, 16 rue Henri Huchard, 75018 Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Biochemistry, 46 rue Henri Huchard, 75018 Paris, France.
authors: Fathi
authors: F
authors: Driss
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France.
authors: Manuel
authors: M
authors: Sanchez
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, 16 rue Henri Huchard, 75018 Paris, France.
authors: Frédéric
authors: F
authors: Fumeron
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, 16 rue Henri Huchard, 75018 Paris, France.
authors: Ronan
authors: R
authors: Roussel
authors: Centre Hospitalier Universitaire de Poitiers, Department of Endocrinology and Diabetology, 2 Rue de la Milétrie, 86021 Poitiers, France; INSERM, Research Unit 1082, 2 Rue de la Milétrie, 86021 Poitiers, France; INSERM, CIC 1402, 2 Rue de la Milétrie, 86021 Poitiers, France; Université de Poitiers, UFR de Médecine et Pharmacie, 6 Rue de la Milétrie, 86073 Poitiers, France.
authors: Samy
authors: S
authors: Hadjadj
authors: Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Avenida Dr. Arnaldo 455, CEP 01246903, São Paulo, SP, Brazil; Centro de Terapia Celular e Molecular (NUCEL/NETCEM) da FMUSP, Avenida Dr. Arnaldo 455, CEP 01246903, São Paulo, SP, Brazil.
authors: Maria Lúcia
authors: ML
authors: Corrêa-Giannella
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, 16 rue Henri Huchard, 75018 Paris, France.
authors: Michel
authors: M
authors: Marre
authors: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, 15 rue de l׳École de Médecine, 75006 Paris, France. Electronic address: gilberto.velho@inserm.fr.
authors: Gilberto
authors: G
authors: Velho
mesh_terms: D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics*; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012306:Risk; D055815:Young Adult
chemical_list: D019255:NADPH Oxidases; C086986:CYBA protein, human
keywords: Advanced oxidation protein products; CYBA gene; Diabetic nephropathy; End-stage renal disease; Genetic association; Myeloperoxidase; NADPH oxidase; Oxidative stress; Prospective cohort study