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Is Glutamate Decarboxylase 2 (GAD2) a Genetic Link between Low Birth Weight and Subsequent Development of Obesity in Children?

Centre National de la Recherche Scientifique 8090-Institute of Biology (D.M., P.B., M.D., M.A., P.F.), Pasteur Institute, 59000 Lille, France; Équipe Avenir 3502 (A.T.), Hôtel-Dieu Hospital, F-75004 Paris, France; Institut National de la Santé et de la Recherce Médicale (INSERM) U563 (B.J., M.T.), Children’s Hospital, 31059 Toulouse Cedex 3, France; INSERM U258-IFR69 (B.H.), Paris Sud Medicine Faculty, 94807 Villejuif, France; Pediatric Endocrine Unit (J.W.), Jeanne de Flandre Hospital, 59000 Lille, France; Department of Pediatric Gastroenterology and Nutrition (P.T.), Trousseau Hospital, 75571 Paris Cedex 12, France; and Imperial College Genome Center and Genomic Medicine (P.F.), Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom

Address all correspondence and requests for reprints to: Philippe Froguel, Imperial College Genome Centre and Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, United Kingdom. E-mail: p.froguel{at}imperial.ac.uk.

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 AG 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 AG 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.

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