THIAGO ANDRADE PATENTE
Projetos de Pesquisa
Unidades Organizacionais
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
10 resultados
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- Plasma extracellular superoxide dismutase concentration, allelic variations in the SOD3 gene and risk of myocardial infarction and all-cause mortality in people with type 1 and type 2 diabetes(2015) MOHAMMEDI, Kamel; BELLILI-MUNOZ, Naima; MARKLUND, Stefan L.; DRISS, Fathi; NAGARD, Herve Le; PATENTE, Thiago A.; FUMERON, Frederic; ROUSSEL, Ronan; HADJADJ, Samy; MARRE, Michel; VELHO, GilbertoBackground: Oxidative stress is involved in development of diabetes complications. Extracellular superoxide dismutase (EC-SOD, SOD3) is a major extracellular antioxidant enzyme and is highly expressed in arterial walls. Advanced oxidation protein products (AOPP) and 8-iso-prostaglandin (isoprostane) are markers of oxidative stress. We investigated association of SOD3 gene variants, plasma concentrations of EC-SOD, AOPP and isoprostane with myocardial infarction and mortality in diabetic patients. Methods: We studied three cohorts designed to evaluate the vascular complications of diabetes: the GENEDIAB study (469 participants with type 1 diabetes at baseline; follow-up data for 259 participants), the GENESIS study (603 participants with type 1 diabetes at baseline; follow-up data for 525 participants) and the DIABHYCAR study (3137 participants with type 2 diabetes at baseline and follow-up). Duration of follow-up was 9, 5, and 5 years, respectively. Main outcome measures were incidence of myocardial infarction, and cardiovascular and total mortality during follow-up. Six single nucleotide polymorphisms in the SOD3 locus were genotyped in the three cohorts. Plasma concentrations of EC-SOD, AOPP, and isoprostane were measured in baseline samples of GENEDIAB participants. Results: In GENEDIAB/GENESIS pooled cohorts, the minor T-allele of rs2284659 variant was inversely associated with the prevalence at baseline (Odds Ratio 0.48, 95% CI 0.29-0.78, p = 0.004) and the incidence during follow-up of myocardial infarction (Hazard Ratio 0.58, 95% CI 0.40-0.83, p = 0.003) and with cardiovascular (HR 0.33, 95% CI 0.08-0.74, p = 0.004) and all-cause mortality (HR 0.44, 95% CI 0.21-0.73, p = 0.0006). The protective allele was associated with higher plasma EC-SOD and lower plasma AOPP concentrations in GENEDIAB. It was also inversely associated with incidence of myocardial infarction (HR 0.75, 95% CI 0.59-0.94, p = 0.01) and all-cause mortality (HR 0.87, 95% CI 0.79-0.97, p = 0.008) in DIABHYCAR. Conclusions: The T-allele of rs2284659 in the promoter of SOD3 was associated with a more favorable plasma redox status and with better cardiovascular outcomes in diabetic patients. Our results suggest that EC-SOD plays an important role in the mechanisms of vascular protection against diabetes-related oxidative stress.
conferenceObject Associations of genetic variants in thioredoxin (TXN) and mitochondrial thioredoxin reductase (TXNRD2) genes with kidney disease in type 1 diabetes(2013) PATENTE, T. A.; MONTEIRO, M. B.; QUEIROZ, M.; NERY, M.; AZEVEDO, M. J.; CANANI, L. H.; PAVIN, E. J.; PARISI, M. C.; MACHADO, U. F.; PASSARELLI, M.; GIANNELLA-NETO, D.; CORREA-GIANNELLA, M. L. C.- Association of a variant in the regulatory region of NADPH oxidase 4 gene and metabolic syndrome in patients with chronic hepatitis C(2015) SIQUEIRA, Erika Rabelo Forte de; PEREIRA, Luciano Beltrao; STEFANO, Jose Tadeu; PATENTE, Thiago; CAVALEIRO, Ana Mercedes; VASCONCELOS, Luydson Richardson Silva; CARMO, Rodrigo Feliciano; PEREIRA, Leila Maria Moreira Beltrao; CARRILHO, Flair Jose; CORREA-GIANNELLA, Maria Lucia; OLIVEIRA, Claudia P.Background: Given the important contribution of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system to the generation of reactive oxygen species induced by hepatitis C virus (HCV), we investigated two single nucleotide polymorphisms (SNPs) in the putative regulatory region of the genes encoding NADPH oxidase 4 catalytic subunit (NOX4) and its regulatory subunit p22phox (CYBA) and their relation with metabolic and histological variables in patients with HCV. Methods: One hundred seventy eight naive HCV patients (49.3% male; 65% HCV genotype 1) with positive HCV RNA were genotyped using specific primers and fluorescent-labeled probes for SNPs rs3017887 in NOX4 and -675 T -> A in CYBA. Results: No association was found between the genotype frequencies of NOX4 and CYBA SNPs and inflammation scores or fibrosis stages in the overall population. The presence of the CA + AA genotypes of the NOX4 SNP was nominally associated with a lower alanine aminotransferase (ALT) concentration in the male population (CA + AA = 72.23 +/- 6.34 U/L versus CC = 100.22 +/- 9.85; mean +/- SEM; P = 0.05). The TT genotype of the CYBA SNP was also nominally associated with a lower ALT concentration in the male population (TT = 84.01 +/- 6.77 U/L versus TA + AA = 109.67 +/- 18.37 U/L; mean +/- SEM; P = 0.047). The minor A-allele of the NOX4 SNP was inversely associated with the frequency of metabolic syndrome (MS) in the male population (odds ratio (OR): 0.15; 95% confidence interval (CI): 0.03 to 0.79; P = 0.025). Conclusions: The results suggest that the evaluated NOX4 and CYBA SNPs are not direct genetic determinants of fibrosis in HCV patients, but nevertheless NOX4 rs3017887 SNP could indirectly influence fibrosis susceptibility due to its inverse association with MS in male patients.
conferenceObject Glutathione peroxidase 1 (GPX1) variants, oxidative stress markers, and risk of kidney complications in patients with type 1 diabetes(2014) MOHAMMEDI, K.; BELLILI-MUNOZ, N.; DRISS, F.; PATENTE, T.; HADJADJ, S.; FUMERON, F.; ROUSSEL, R.; CORREA-GIANNELLA, M.; MARRE, M.; VELHO, G.- Association of single nucleotide polymorphisms in the gene encoding GLUT1 and diabetic nephropathy in Brazilian patients with type 1 diabetes mellitus(2015) MARQUES, T.; PATENTE, T. A.; MONTEIRO, M. B.; CAVALEIRO, A. M.; QUEIROZ, M. S.; NERY, M.; AZEVEDO, M. J. de; CANANI, L. H.; PARISI, M. C.; MOURA-NETO, A.; PASSARELLI, M.; GIANNELLA-NETO, D.; MACHADO, U. F.; CORREA-GIANNELLA, M. L.Mesangial cells subject to high extracellular glucose concentrations, as occur in hyperglycaemic states, are unable to down regulate glucose influx, resulting in intracellular activation of deleterious biochemical pathways. A high expression of GLUT1 participates in the development of diabetic glomerulopathy. Variants in the gene encoding GLUT1 (SLC2A1) have been associated to this diabetic complication. The aim of this study was to test whether polymorphisms in SLC2A1 confer susceptibility to diabetic nephropathy (DN) in Brazilian type I diabetes patients. Four polymorphisms (rs3820589, rs1385129, rs841847 and rs841848) were genotyped in a Brazilian cohort comprised of 452 patients. A prospective analysis was performed in 155 patients. Mean duration of follow-up was 5.6 +/- 2.4 years and the incidence of renal events was 18.0%. The rs3820589 presented an inverse association with the prevalence of incipient DN (OR: 0.36,95% CI: 0.16 - 0.80, p = 0.01) and with progression to renal events (HR: 0.20; 95% CI: 0.03 - 0.70; p = 0.009). AGGT and AGAC haplotypes were associated with the prevalence of incipient ON and the AGAC haplotype was also associated with the prevalence of established/advanced DN. In conclusion, rs3820589 in the SLC2A1 gene modulates the risk to DN in Brazilian patients with inadequate type I diabetes control.
- Allelic variations in the CYBA gene of NADPH oxidase and risk of kidney complications in patients with type 1 diabetes(2015) PATENTE, Thiago A.; MOHAMMEDI, Kamel; BELLILI-MUNOZ, Naima; DRISS, Fathi; SANCHEZ, Manuel; FUMERON, Frederic; ROUSSEL, Ronan; HADJADJ, Samy; CORREA-GIANNELLA, Maria Lucia; MARRE, Michel; VELHO, GilbertoOxidative 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% Cl 1.17-2.18, P=0.003) in SURGENE. The same allele was associated with established/advanced nephropathy (OR 1.52, 95% Cl 1.22-1.92, P=0.0001) and with the incidence of end-stage renal disease (ESRD) (HR 2.01, 95% Cl 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.
- Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G > A variant with type 1 diabetes in a Brazilian cohort(2015) PATENTE, Thiago A.; MONTEIRO, Maria B.; VIEIRA, Suzana M.; SILVA, Maria E. Rossi da; NERY, Marcia; QUEIROZ, Marcia; AZEVEDO, Mirela J.; CANANI, Luis H.; PARISI, Maria C.; PAVIN, Elizabeth J.; MAINARDI, Debora; JAVOR, Juraj; VELHO, Gilberto; COIMBRA, Cassio N.; CORREA-GIANNELLA, Maria LuciaBackground: A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association.. Methods: 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HIA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. Results: Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69,95% Cl 133-2.15, p < 0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% Cl 3.23-8.59, p < 0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% Cl 1.21-7.21, p = 0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14,95% Cl 1.02-4.50, p = 0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. Conclusion: Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D.
- Catalase activity, allelic variations in the catalase gene and risk of kidney complications in patients with type 1 diabetes(2013) MOHAMMEDI, Kamel; PATENTE, Thiago A.; BELLILI-MUNOZ, Naiema; DRISS, Fathi; MONTEIRO, Maria Beatriz; ROUSSEL, Ronan; PAVIN, Elizabeth J.; SETA, Nathalie; FUMERON, Frederic; AZEVEDO, Mirela J.; CANANI, Luis H.; HADJADJ, Samy; MARRE, Michel; CORREA-GIANNELLA, Maria Lucia; VELHO, GilbertoOxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the G,n,tique de la N,phropathie Diab,tique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney.
conferenceObject NADPH OXIDASE (NOX 4) AND P22PHOX GENE POLYMORPHISMS ARE ASSOCIATED WITH HUMAN NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)(2014) RABELO, F.; STEFANO, J. T.; LIMA, R. V.; SEIXAS, M.; PATENTE, T.; VANNI, D.; CAVALEIRO, A. M.; MAZO, D. C.; CARRILHO, F. J.; CORREA-GIANNELLA, M. L.; OLIVEIRA, C.- 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(2013) MONTEIRO, M. B.; PATENTE, T. A.; MOHAMMEDI, K.; QUEIROZ, M. S.; AZEVEDO, M. J.; CANANI, L. H.; PARISI, M. C.; MARRE, M.; VELHO, G.; CORREA-GIANNELLA, M. L.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.