| Domaine : |
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Sciences du Vivant/Génétique/Génétique humaine
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PMID (identifiant
de la référence Pubmed) : |
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 (14691540)  |
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| Titre : |
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GAD2 on chromosome 10p12 is a candidate gene for human obesity. |
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| Auteur(s) : |
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Philippe Boutin1, Christian Dina1, Francis Vasseur1, 2, Séverine Dubois1, Laetitia Corset1, Karin Séron1, Lynn Bekris3, Janice Cabellon3, Bernadette Neve1, Valérie Vasseur-Delannoy1, Mohamed Chikri1, 2, Marie-Aline Charles4, Karine Clement5, Ake Lernmark3, Philippe Froguel ( ) 1, 6 |
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| Laboratoire : |
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| Résumé : |
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The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity. |
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Langue du texte
intégral : |
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Anglais |
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| Type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1371/journal.pbio.0000068 |
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| Journal : |
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| Audience : |
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non spécifiée |
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| Date de publication : |
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12/2003 |
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Date de publication
électronique : |
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03/11/2003 |
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| Volume : |
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1 |
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| Numéro : |
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3 |
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| Page, identifiant, ... : |
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E68 |
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| Descripteur(s) MeSH : |
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Adult – Aged – Alleles – Autoantibodies – Case-Control Studies – Catalysis – Cell Line – Chromosome Mapping – Chromosomes – Human – Pair 10 – Eating – Family Health – Feeding Behavior – Female – Genotype – Glutamate Decarboxylase – Haplotypes – Humans – Hunger – Insulin – Insulin-Secreting Cells – Isoenzymes – Linkage (Genetics) – Lod Score – Luciferases – Male – Middle Aged – Molecular Sequence Data – Neuropeptide Y – Obesity – Morbid – Odds Ratio – Paraventricular Hypothalamic Nucleus – Plasmids – Polymorphism – Single Nucleotide – Promoter Regions (Genetics) – Questionnaires – Risk – gamma-Aminobutyric Acid |
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