Guilherme Coutinho Kullmann Duarte

The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus

It is well established that genetic factors play an important role in the development of both type 2 diabetes mellitus (DM2) and obesity, and that genetically susceptible subjects can develop these metabolic diseases after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2 and/or obesity. Uncoupling protein 1 (UCP1) is mainly expressed in brown adipose tissue, and acts in thermogenesis, regulation of energy expenditure, and protection against oxidative stress. All these mechanisms are associated with the pathogenesis of DM2 and obesity. Hence, UCP1 is a candidate gene for the development of these disorders. Indeed, several studies have reported that polymorphisms -3826A/G, -1766A/G and -112A/C in the promoter region, Ala64Thr in exon 2 and Met299Leu in exon 5 of UCP1 gene are possibly associated with obesity and/or DM2. However, results are still controversial in different populations. Thus, the aim of this study was to review the role of UCP1 in the development of these metabolic diseases.

The UCP1 −3826A/G Polymorphism Is Associated with Diabetic Retinopathy and Increased UCP1 and MnSOD2 Gene Expression in Human Retina

PURPOSE Uncoupling protein 1 (UCP1) reduces mitochondrial production of reactive oxygen species (ROS). ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Therefore, deleterious polymorphisms in the UCP1 gene are candidate risk factors for DR. We investigated the relationships between the UCP1 -3826A/G polymorphism and risk of DR and UCP1 gene expression in human retina. Considering that superoxide dismutase-2 (MnSOD2) enzyme is the first line of defense against oxidative stress in mitochondria, we also analyzed MnSOD2 gene expression in retinal samples according to different UCP1 -3826A/G genotypes. METHODS In a case-control study, frequencies of -3826A/G polymorphisms were analyzed in 257 type 1 DM patients (154 cases with DR and 103 controls without DR). In a cross-sectional study comprising cadaveric cornea donors, UCP1 and MnSOD2 gene expressions were evaluated in 107 retinal samples differentiated according to different -3826A/G genotypes. RESULTS In the type 1 DM group, multivariate analysis confirmed that the G/G genotype was an independent risk factor for DR (OR = 3.503; P = 0.043). In cornea donors, G allele carriers had higher UCP1 cDNA and protein concentrations than A/A carriers (P = 0.034 and P = 0.039, respectively). Interestingly, G allele carriers exhibited increased MnSOD2 expression (P = 0.001). CONCLUSIONS This study suggests that the -3826A/G polymorphism is associated with DR in type 1 DM patients. This is the first report demonstrating UCP1 gene expression in human retinas and indicates that the -3826A/G polymorphism influences its expression. In addition, the -3826G allele was associated with increased MnSOD2 expression; thus, suggesting that this allele could be a marker of oxidative stress.

The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil

OBJECTIVE The aim of this study was to investigate the association between the rs7903146 (C/T) polymorphism in the TCF7L2 gene and type 2 diabetes mellitus, in a Southern-Brazilian population. MATERIALS AND METHODS The TCF7L2 rs7903146 polymorphism was genotyped in 953 type 2 diabetic patients and 535 non-diabetic subjects. All subjects were white. The polymorphism was genotyped by Real-Time PCR using TaqMan MGB probes (Life Technologies). Odds ratios (OR) and 95% confidence intervals (CI) were calculated for additive, recessive and dominant inheritance models. RESULTS Genotype and allele frequencies of the rs7903146 polymorphism differed significantly between type 2 diabetic patients and non-diabetic subjects (P = 0.001 and P = 0.0001, respectively). The frequency of the minor allele was 38% in type 2 diabetes group and 31% in non-diabetic subjects, and this allele was significantly associated with type 2 diabetes risk (OR = 1.42, 95% CI 1.15 - 1.76 for the dominant model of inheritance). Moreover, the T/T genotype was associated with a higher risk for type 2 diabetes (OR = 1.83, 95% CI 1.3-2.5) than the presence of only one copy of the T allele (OR = 1.31, 95% CI 1.1-1.6). Both results were adjusted for age and gender. CONCLUSIONS Our results confirm the association between the TCF7L2 rs7903146 polymorphism and increase risk for type 2 diabetes in Southern-Brazil.

The rs2292239 polymorphism in ERBB3 gene is associated with risk for type 1 diabetes mellitus in a Brazilian population

The Erb-b2 receptor tyrosine kinase 3 (ERBB3) belongs to a family of epidermal growth factor receptors of protein tyrosine kinases, and regulates cell survival, differentiation and proliferation in several cell types. Previous studies have suggested that ERBB3 contributes to T1DM pathogenesis by modulating antigen presenting cell function, autoimmunity and cytokine-induced beta-cell apoptosis. Accordingly, some genome-wide association studies identified ERBB3 gene as a susceptibility locus for T1DM, with the strongest association signal being observed for the rs2292239 single nucleotide polymorphism (SNP) in intron 7 of the gene. Therefore, the aim of the present study was to replicate the association of the ERBB3 rs2292239 SNP with T1DM in a Brazilian population. We analyzed 421 T1DM patients (cases) and 510 nondiabetic subjects (controls). All subjects were self-declared as white. The ERBB3 rs2292239 (A/C) SNP was genotyped by real-time PCR using TaqMan MGB probes. Genotype (P=0.001) and allele (P=0.002) frequencies of the ERBB3 rs2292239 SNP were differently distributed between T1DM patients and nondiabetic controls. Moreover, the A allele was significantly associated with risk for T1DM when considering recessive (OR=1.58, 95% CI 1.11-2.27; P=0.015), additive (OR=1.78, 95% CI 1.21-2.62; P=0.004), and dominant (OR=1.39, 95% CI 1.07-1.81; P=0.016) models of inheritance. However, after adjustment for presence of high-risk HLA DR/DQ genotypes, the rs2292239 SNP remained independently associated with T1DM only for the additive model (OR=1.62, 95% CI 1.02-2.59; P=0.043). Our results suggest that the A/A genotype of the ERBB3 rs2292239 SNP is associated with risk for T1DM in a white Brazilian population.

RS2910164 polymorphism in the microrna-146a is associated with risk for type 1 diabetes mellitus

Background Type 1 diabetes mellitus (T1D) is characterized by severe autoimmune destruction of pancreatic beta-cells, which renders subjects insulin-dependent for life. The triggering of autoimmunity against beta-cells is probably caused by a combination of environmental and genetic risk factors. Even though much is known about the genetic of T1D, more information is needed to completely unravel this tangled web. MicroRNAs (miRNAs) are a class of small noncoding RNAs molecules that negatively regulate gene expression by inducing target mRNA cleavage or by inhibiting protein translation. Abnormal miRNA expressions have been described in several pathological conditions, including autoimmune diseases. Single nucleotide polymorphisms (SNPs) in genes codifying miRNAs may alter the expression of the corresponding miRNA and, thus, confer susceptibility for a given disease. In this context, two SNPs in the miR-146a gene, rs2910164 and rs57095329, have been reported as being associated with autoimmune diseases by altering the expression of the mature miR-146a, a miRNA involved in both innate and adaptive immunity.

Evaluation of high-risk type 1 diabetes HLA-DR and DQ haplotypes using three single nucleotide polymorphisms in a population from Southern Brazil

Background Type 1 diabetes mellitus (T1D) accounts for ~10% of all diabetes cases, and it is caused by autoimmune destruction of pancreatic beta-cells, which leads to insulin deficiency and fates individuals to require insulin treatment to survive. The triggering of autoimmunity against betacells is caused by interaction between environmental and genetic risk factors. Among the several loci associated with T1D, the human leukocyte antigen (HLA) class II DR/DQ locus is the main genetic risk factor for T1D, accounting for 30-50% of genetic risk for this disease. Other genes have been associated with minor effects on T1D risk when compared with HLA, with different studies indicating that the effect of non-HLA polymorphisms on predisposition for T1D may be different according to HLA DR/DQ types. In this scenario, a recent study identified a minimum set of three polymorphisms (rs3104413, rs2854275, rs9273363) which can predict high-risk HLA-DR/DQ types relevant to T1D.