Variantes no gene da adiponectina (AdipoQ): relações com adiponectina e Diabetes Mellitus tipo 2 em nipo-brasileiros

• Autor(a) principal: Vendramini, Marcio Faleiros [UNIFESP]
• Data de Publicação: 2007
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UNIFESP
• dARK ID: ark:/48912/0013000013p5f
• Texto Completo: http://repositorio.unifesp.br/handle/11600/23826
• topic: Adiponectina/genética; Diabetes mellitus tipo 2; Adiponectin/genetics; Diabetes mellitus, type 2

Artigo 1: Plasma adiponectin levels and incident glucose intolerance in Japanese–Brazilians: A seven-year follow-up study (The objective of this study was to investigate whether decreased baseline adiponectin levels are an independent risk factor for development of glucose intolerance in a population-based study of Japanese–Brazilians, a group with one of the highest prevalence rates of diabetes worldwide. We examined 210 Japanese–Brazilians (97 male and 113 female, aged 56.7 ± 10.1 years) with normal glucose tolerance (NGT). Plasma adiponectin, insulin, fasting and 2-h plasma glucose and lipid profile were evaluated at baseline and also at 7-year follow-up. Plasma adiponectin levels were significantly lower in glucose intolerance progressors compared with subjects who remained NGT. By increasing tertiles of adiponectin, the frequencies of subjects who progressed to glucose intolerance were 40%, 33% and 27% and the frequencies of subjects who remained NGT were 13%, 35% and 52% (÷2 = 15.8, p = 0.001). Logistic regression analyses showed that adiponectin levels (OR for the highest versus lowest tertile: 0.31; 95% CI: 0.12–0.84, p = 0.021), male sex (OR: 2.61, 95% CI: 1.21–5.65, p = 0.015), fasting plasma glucose (OR: 3.05, 95% CI: 1.35–6.91, p = 0.008) and waist circumference (OR: 1.04, 95% CI: 1.00–1.08, p = 0.046) were independent risk factors for the progression to glucose intolerance. In conclusion, low plasma levels of adiponectin is one of several independent predictors of glucose intolerance in a Japanese–Brazilian population).Artigo 2: Association of genetic variants in the adiponectin encoding gene (ADIPOQ) with type 2 diabetes in Japanese-Brazilians (Aim: To assess the contribution of ADIPOQ variants to type 2 diabetes in Japanese-Brazilians. Methods: we genotyped 200 patients with diabetes mellitus (100 male and 100 female, aged 55.5 ± 10.8 years) and 200 control subjects with NGT (72 male and 128 female, aged 54.0 ± 13.4 years). Results: whereas each polymorphism studied (T45G, G276T and A349G) was not significantly associated with type 2 diabetes mellitus, the haplotype GGA was over-represented in our diabetic population (9.3% against 3.1% in NGT individuals, p = 0.0003). Also, this haplotype was associated with decreased levels of adiponectin. We also identified three mutations in exon 3: I164T, R221S and H241P but, owing the low frequencies of them, associations with type 2 diabetes could not be evaluated. The subjects carrying the R221S mutation had plasma adiponectin levels lower than those without the mutation (1.97 ± 0.80 ìg/ml vs 8.08 ± 6.27 ìg/ml, p= 0.015). Similarly, the I164T mutation carriers had mean plasma adiponectin levels lower than those non-carriers (3.73 ± 0.88 ìg/ml vs 8.08 ± 6.27 ìg/ml) but this difference was not significant (p= 0.23). Conclusions: we identified in the ADIPOQ gene a risk haplotype for type 2 diabetes that affects plasma adiponectin levels in the Japanese-Brazilian population).Artigo 3: A Novel Mutation in the Adiponectin (ADIPOQ) Gene is Associated with Hypoadiponectinemia in Japanese-Brazilians (Objective: Adiponectin, an important mediator of insulin sensitivity, is encoded by the ADIPOQ gene. Here we describe two Japanese-Brazilian families with hypoadiponectinemia due to a novel mutation on ADIPOQ gene. Design and Patients: In this study, we examined the entire translated regions of adiponectin in Japanese-Brazilians, a population with one of the highest prevalence rates of diabetes worldwide. We screened 200 patients with type 2 diabetes and 240 age-matched subjects with normal glucose tolerance. Results: A novel heterozygous T deletion at position 186 in exon 2 of the ADIPOQ gene, causing a frameshift at codon 62 leading to a premature termination at codon 168 (p.Gly63ValfsX106) was found in two individuals with diabetes. This mutation was not found in 240 nondiabetic control subjects. In addition, we screened the mutation in an expanded set of 100 nondiabetic subjects from general Brazilian population, but we found no mutation. Six additional mutation carriers family members of probands were identified. Mutation-carrier individuals had markedly low plasma adiponectin concentrations compared with those without the mutation (DM: 1.01 ± 0.69 ìg/ml vs 6.49 ± 5.04 ìg/ml, p< 0.001; NGT: 1.10 ± 0.49 ìg/ml vs 10.36 ± 6.63 ìg/ml, p= 0.003). All individuals carrying the p.Gly63ValfsX106 mutation and older than 30 years were found to be diabetic. Conclusions: We describe for the first time a frameshift mutation in exon 2 of the ADIPOQ gene, which modulates adiponectin levels and may contribute to the genetic risk of late-onset diabetes in Japanese-Brazilians)..