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1.
Nat Genet ; 37(8): 863-7, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16025115

RESUMO

We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Teste de Tolerância a Glucose , Obesidade/genética , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Adulto , Estudos de Casos e Controles , Criança , Haplótipos , Humanos , RNA Mensageiro/genética
2.
J Clin Endocrinol Metab ; 90(4): 2384-90, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15671113

RESUMO

Low birth weight is a risk factor for obesity and type 2 diabetes. The fetal insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for glucokinase, the ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes. Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior.


Assuntos
Peso ao Nascer , Glutamato Descarboxilase/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Estatura , Índice de Massa Corporal , Criança , Comportamento Alimentar , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Insulina/metabolismo , Secreção de Insulina , Masculino
3.
Arch Cardiovasc Dis ; 103(1): 10-8, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20142115

RESUMO

BACKGROUND: Many studies performed in adults have reported the involvement of genetic determinants in vascular alterations that predispose to cardiovascular diseases later in life. To date, no study has assessed the co-involvement of gene polymorphisms as cardiovascular risk factors in children. AIMS: To search for variants involved in early vascular alterations in obese children. METHODS: In 232 obese children, we performed an association study between variables related to endothelial function or arterial mechanical properties and functional variants reported to predispose towards vascular alterations in adults. Candidate polymorphisms were selected in genes involved in the renin-angiotensin system, vascular endothelial cell remodelling and communication, arterial inflammation, adiponectin production and lipoprotein metabolism. Non-invasive arterial measurements were performed to evaluate the mechanical characteristics of the common carotid artery and the endothelial function of the brachial artery. RESULTS: We found no association between the polymorphisms studied, taken alone or in combination with the arterial variables measured. CONCLUSION: Our hypothesis predicting that the tested genetic variants, which are involved in adult cardiovascular diseases, may influence the susceptibility to early vascular alterations in obese children was not validated. Thus, obesity-associated metabolic complications appear to remain the main predictors of arterial alterations in obese children.


Assuntos
Obesidade/genética , Polimorfismo Genético , Doenças Vasculares/genética , Adolescente , Artéria Braquial/fisiopatologia , Artéria Carótida Primitiva/fisiopatologia , Criança , Complacência (Medida de Distensibilidade) , Endotélio Vascular/fisiopatologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Obesidade/complicações , Obesidade/diagnóstico por imagem , Obesidade/fisiopatologia , Fenótipo , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Ultrassonografia , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/fisiopatologia , Vasodilatação
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