GAD2 on chromosome 10p12 is a candidate gene for human obesity

Philippe Boutin, Christian Dina, Francis Vasseur, Séverine Dubois, Laetitia Corset, Karin Séron, Lynn Bekris, Janice Cabellon, Bernadette Neve, Valérie Vasseur-Delannoy, Mohamed Chikri, M. Aline Charles, Karine Clement, Ake Lernmark, Philippe Froguel

Research output: Contribution to journalArticle

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Abstract

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 γ-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 (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, 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 b cells, we analyzed GAD65 antibody level as a marker of β-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 β-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.

Original languageEnglish
JournalPLoS Biology
Volume1
Issue number3
DOIs
Publication statusPublished - 1 Dec 2003
Externally publishedYes

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Chromosomes
Polymorphism
single nucleotide polymorphism
Single Nucleotide Polymorphism
obesity
Nucleotides
Obesity
Genes
chromosomes
Aminobutyrates
Morbid Obesity
genes
Eating
insulin secretion
Insulin
Haplotypes
food intake
acids
haplotypes
Alleles

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Boutin, P., Dina, C., Vasseur, F., Dubois, S., Corset, L., Séron, K., ... Froguel, P. (2003). GAD2 on chromosome 10p12 is a candidate gene for human obesity. PLoS Biology, 1(3). https://doi.org/10.1371/journal.pbio.0000068

GAD2 on chromosome 10p12 is a candidate gene for human obesity. / Boutin, Philippe; Dina, Christian; Vasseur, Francis; Dubois, Séverine; Corset, Laetitia; Séron, Karin; Bekris, Lynn; Cabellon, Janice; Neve, Bernadette; Vasseur-Delannoy, Valérie; Chikri, Mohamed; Charles, M. Aline; Clement, Karine; Lernmark, Ake; Froguel, Philippe.

In: PLoS Biology, Vol. 1, No. 3, 01.12.2003.

Research output: Contribution to journalArticle

Boutin, P, Dina, C, Vasseur, F, Dubois, S, Corset, L, Séron, K, Bekris, L, Cabellon, J, Neve, B, Vasseur-Delannoy, V, Chikri, M, Charles, MA, Clement, K, Lernmark, A & Froguel, P 2003, 'GAD2 on chromosome 10p12 is a candidate gene for human obesity', PLoS Biology, vol. 1, no. 3. https://doi.org/10.1371/journal.pbio.0000068
Boutin P, Dina C, Vasseur F, Dubois S, Corset L, Séron K et al. GAD2 on chromosome 10p12 is a candidate gene for human obesity. PLoS Biology. 2003 Dec 1;1(3). https://doi.org/10.1371/journal.pbio.0000068
Boutin, Philippe ; Dina, Christian ; Vasseur, Francis ; Dubois, Séverine ; Corset, Laetitia ; Séron, Karin ; Bekris, Lynn ; Cabellon, Janice ; Neve, Bernadette ; Vasseur-Delannoy, Valérie ; Chikri, Mohamed ; Charles, M. Aline ; Clement, Karine ; Lernmark, Ake ; Froguel, Philippe. / GAD2 on chromosome 10p12 is a candidate gene for human obesity. In: PLoS Biology. 2003 ; Vol. 1, No. 3.
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