GAD2 on Chromosome 10p12 Is a Candidate Gene for Human Obesity

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 β 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.

Mouse Models and the Genetics of Diabetes

“…Glucokinase (GCK) is an example of one such ␤-cell essential gene linked to both type 1 and type 2 diabetes (7,8). Although GAD65 is considered a major ␤-cell autoantigen in type 1 diabetes, genetic association with the gene encoding it (GAD2) has been with obesity, the major risk factor for type 2 diabetes (9). Indeed, when specific candidate genes identified in either type 1 or type 2 diabetes are screened for association/linkage in the other disease form, evidence for overlap is rare (10).…”

Several obesity- and nutrient-related gene polymorphisms but not FTO and UCP variants modulate postabsorptive resting energy expenditure and fat-induced thermogenesis in obese individuals: the NUGENOB Study

“…These data suggest that HSD11B1 G4A, GAD2 À243 A4G and LIPC 644 A4G may influence postabsorptive REE independent of changes in body composition, indicating an effect on adaptive thermogenesis 7 Conflicting data have been reported with respect to associations between SNPs in GAD2 and CART and obesity. [18][19][20][21] These opposing findings may partly be due to effects of GAD2 À243 A4G on both energy intake (higher hunger and disinhibition scores) 19 and, based on the present data, increased postabsorptive REE. CART is an anorectic peptide that is expressed in hypothalamic areas and is involved in the control of feeding behaviour.…”

ENPP1, premier exemple d’un déterminant génétique commun à l’obésité et au diabète de type 2

“…Cette obésité à fort impact délétère métabolique s'accompagne d'infarctus du myocarde précoces chez des diabétiques porteurs de la mutation Q121 d'ENPP1 [20]. Les résultats actuels, obtenus à partir de l'étude de plus de 6 000 personnes [21], montrent qu'au-delà des perturbations de la prise alimentaire et de la satiété [22][23][24][25], il existe des obésités d'origine « métabolique ». Ces obésités devront être prévenues ou prises en charge de manière différente que celles liées à des troubles du comportement alimentaire.…”