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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

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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

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Título 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
Autor Vieira, Suzana Maria de Souza
Monteiro, Maria Beatriz Camargo de Almeida
Marques, Tatiana
Luna, Ana M.
Fortes, Maria Angela Henriques Zanella
Nery, Márcia
Queiroz, Márcia Silva
Dib, Sérgio Atala
Vendramini, Marcio Faleiros
Azevedo, Mirela Jobim de
Canani, Luis Henrique Santos
Parisi, Maria Cândida Ribeiro
Pavin, Elizabeth João
Giannella Neto, Daniel
Giannella, Maria Lucia Cardillo Corrêa
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.
Contido em BMC medical genetics. London, BioMed Central. Vol. 12, no. 129 (Sep. 2011), p. 1-6
Assunto Diabetes mellitus tipo 1
Estresse oxidativo
Estudos de casos
Rim : Patologia
Origem Estrangeiro
Tipo Artigo de periódico
URI http://hdl.handle.net/10183/109968
Arquivos Descrição Formato
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